WO2024036329A2 - Cytotoxic compounds and conjugates thereof - Google Patents

Cytotoxic compounds and conjugates thereof Download PDF

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Publication number
WO2024036329A2
WO2024036329A2 PCT/US2023/072120 US2023072120W WO2024036329A2 WO 2024036329 A2 WO2024036329 A2 WO 2024036329A2 US 2023072120 W US2023072120 W US 2023072120W WO 2024036329 A2 WO2024036329 A2 WO 2024036329A2
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compound
drug
alkylene
ligand
salt
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PCT/US2023/072120
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French (fr)
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WO2024036329A3 (en
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Philip MOQUIST
Svetlana Doronina
Nicole DUNCAN
Gabriele BLAHNIK-FAGAN
Sharsti SANDALL
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Seagen Inc.
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Publication of WO2024036329A2 publication Critical patent/WO2024036329A2/en
Publication of WO2024036329A3 publication Critical patent/WO2024036329A3/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68031Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being an auristatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545Heterocyclic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549Sugars, nucleosides, nucleotides or nucleic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06017Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06052Val-amino acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06017Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • C07K5/06069Ser-amino acid
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10Tetrapeptides
    • C07K5/1002Tetrapeptides with the first amino acid being neutral
    • C07K5/1005Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu

Definitions

  • cytotoxic agents have been investigated for the targeted delivery of cytotoxic agents to tumor cells, including oligopeptides, antibodies, and other proteins. While various drug classes have been evaluated for targeted delivery by these ligands, only a few drug classes have proved sufficiently active as Ligand-Drug Conjugates, while having a suitable toxicity profile and other pharmacological properties, to warrant clinical development. There is thus a need for additional cytotoxic agents with improved toxicity profile and other pharmacological properties.
  • R 1 , R 3 , and R 4 are independently H or C 1 -C 4 alkyl;
  • R 6 is C 1 -C 4 alkyl optionally substituted with OH;
  • R 7 is H, C 1 -C 4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl;
  • E is phenyl or 5-6 membered heteroaryl;
  • R 8 , R 9 , and R 11 are each independently H or OH;
  • n is 0, 1, or 2; and q is 0 or 1.
  • q is 0.
  • q is 1.
  • R 11 is H. In some embodiments, R 11 is OH.
  • X is OH. In some embodiments, X is -C(O)NR a R b , -S(O) 2 R a , -S(O)-R a -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X b is -NR 1 R 2 and X a is . In some embodiments, R 3 is H. In some embodiments, R 4 is H. In some embodiments, n is 0 or 1.
  • X a and X b are taken together with the carbon atom to which they are attached to form , wherein the asterisk denotes the carbon atom of Formula (I) that bears the X a and X b groups.
  • m is 2 or 3.
  • R 1 is H.
  • R 1 is C 1 -C 4 alkyl.
  • R 1 is methyl.
  • R 2 is methyl.
  • R 10 is H.
  • R 10 is methyl.
  • R 6 is unsubstituted C 1 -C 4 alkyl.
  • R 6 is isopropyl. In some embodiments, R 6 is C 1 -C 4 alkyl substituted with OH. In some embodiments, R 7 C 1 -C 4 alkyl substituted with OH. In some embodiments, R 7 is -CH 2 OH. In some embodiments, R 7 is H. In some embodiments, R 7 is unsubstituted C 1 -C 4 alkyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is 5-6 membered heteroaryl. In some embodiments, R 8 is H. In some embodiments, R 8 is OH. In some embodiments, E is phenyl.
  • E-R 9 is , wherein the wavy line indicates the point of attachment of E to the rest of the compound. In some embodiments, E is 5-6 membered heteroaryl. In some embodiments, R 9 is H. In some embodiments, R 9 is OH. [0010] In some embodiments of Formula (I), X b is -NR 1 R 2 ; R 1 is H or methyl; R 2 is methyl; X is OH; R 3 and R 4 are H; R 6 is is isopropyl; R 7 is -CH 2 OH; R 8 is H; E is phenyl; and R 9 is H. [0011] In some embodiments of Formula (I), the compound is or a salt thereof.
  • the compound is a compound of Table 1.
  • a Drug-Linker compound of the following formula: Q-D, or a salt thereof wherein Q is a Linker Unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S * -RL-, (iv) Z'-A-S * -RL-Y-, (v) Z'-A-B(S * )-RL-, (vi) Z'-A-B(S * )-RL-Y-, (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-;
  • Z' is a Stretcher Unit precursor;
  • A is a Linker Unit selected from the group consisting of:
  • the Linker Unit Q is of formula (i), (ii), (iii), (iv), (x), or (xi). In some embodiments, the Linker Unit Q is of formula (v), (vi), (ix), or (xi). In some embodiments, the Linker Unit Q is of formula (viii), (ix), (x), or (xi).
  • the Stretcher Unit Z' is wherein R 17 is –CH 2 CH 2 (OCH 2 CH 2 )k–, -C 1 -C 10 alkylene-, C 1 -C 10 heteroalkylene-, -C 3 -C 8 carbocyclo-, -O-(C 1 -C 8 alkylene)-, -arylene-, -C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, -(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, -C 3 -C 8 heterocyclo-, -C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, -(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene- , -C 1 -C 10 alkylene-, -
  • the Stretcher Unit Z' is an integer of from 1-4 and each R a is independently selected from the group consisting of C 1-6 alkyl and C 1-6 haloalkyl, or two R a groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group; and the wavy line indicates the point of covalent attachment to the rest of the Drug-Linker compound.
  • the Stretcher Unit Z' is
  • the Connector Unit A is c is an integer ranging from 1 to 6; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof.
  • A is a bond.
  • each AA is independently a proteinogenic or non-proteinogenic amino acid; and the wavy lines indicate points of attachment to the rest of the Drug-Linker compound or salt thereof.
  • B is an amino acid. In some embodiments, B is
  • the wavy line indicates the point of attachement to the Partitioning Agent S*; and the asterisks indicate points of attachment to the rest of the Drug-Linker structure.
  • the Partitioning Agent S * is a polyethylene glycol (PEG) unit, cyclodextrin unit, polyamide, hydrophilic peptide, polysaccharide, or dendrimer.
  • Partitioning Agent S * is a PEG Unit comprising from 4 to 72 (CH 2 CH 2 O) subunits.
  • the PEG Unit is ; b is selected from the group consisting of 4 to 36; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof.
  • the Releasable Linker RL is –(AA) 1-12 –; and each AA is independently a proteinogenic or non-proteinogenic amino acid. [0024] In some embodiments, the Releasable Linker RL is –AA 1 -AA 2 – or –AA 1 -AA 2 -AA 3 –, wherein AA 1 is attached to the Stretcher Unit Z' or the Connector Unit A. In some embodiments, the Releasable Linker RL is
  • the Releasable Linker RL is a glycoside.
  • the Releasable Linker RL is wherein Su is a hexose form a monosaccharide; O' represents the oxygen atom of a glycosidic bond that is capable of cleavage by a glycosidase; the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.
  • the Releasable Linker RL is the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.
  • the Spacer Unit Y is wherein EWG is an electron-withdrawing group; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof.
  • the Spacer Unit Y is the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof.
  • Z' is R 17 is C 1 -C 10 alkylene; A is a bond; RL is –AA 1 -AA 2 –; AA1 and AA2 are each independently a proteinogenic amino acid; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof.
  • Z' is A is a bond; RL is and Y is [0031]
  • Y-D is and the wavy line indicates the site of attachment to the rest of the Drug-Linker compound or salt thereof.
  • Y-D is and the wavy line indicates the site of attachment to the rest of the Drug-Linker compound or salt thereof.
  • the compound is or a salt thereof.
  • the compound is or or a salt thereof.
  • the Drug-Linker compound is a compound of Table 2.
  • the Linker Unit Q is of formula (i), (ii), (iii), (iv), (x), or (xi). In some embodiments, the Linker Unit Q is of formula (v), (vi), (ix), or (xi). In some embodiments, the Linker Unit Q is of formula (viii), (ix), (x), or (xi).
  • the Ligand Unit L and the Stretcher Unit Z together are , wherein R 17 is –CH 2 CH 2 (OCH 2 CH 2 )k–, -C 1 -C 10 alkylene-, C 1 -C 10 heteroalkylene-, -C 3 -C 8 carbocyclo-, -O-(C 1 -C 8 alkylene)-, -arylene-, -C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, -(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, -C 3 - C 8 heterocyclo-, -C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, -(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-, -(C 3 -C
  • the Ligand Unit L and the Stretcher Unit Z together are independently selected from the group consisting of C 1-6 alkyl and C 1-6 haloalkyl, or two R a groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group; and the wavy line indicates the point of covalent attachment to the rest of the Ligand-Drug Conjugate compound.
  • the Ligand Unit L and the Stretcher Unit Z together are independently selected from the group consisting of C 1-6 alkyl and C 1-6 haloalkyl, or two R a groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group; and the wavy line indicates the point of covalent attachment to the rest of the Ligand-Drug Conjugate compound.
  • the Connector Unit A is c is an integer ranging from 1 to 6; and the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
  • A is a bond.
  • each AA is independently a proteinogenic or non-proteinogenic amino acid; and the wavy lines indicate points of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
  • B is an amino acid.
  • B is the wavy line indicates the point of attachement to the Partitioning Agent S*; and the asterisks indicate points of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
  • the Partitioning Agent S * is a polyethylene glycol (PEG) unit, cyclodextrin unit, polyamide, hydrophilic peptide, polysaccharide, or dendrimer.
  • the Partitioning Agent S * is a PEG Unit comprising from 4 to 72 (CH 2 CH 2 O) subunits.
  • the PEG Unit is ; b is selected from the group consisting of 4 to 36; and the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
  • the Releasable Linker RL is –(AA) 1-12 –; and each AA is independently a proteinogenic or non-proteinogenic amino acid.
  • the Releasable Linker RL is –AA1-AA2– or –AA 1 -AA 2 -AA 3 –, wherein AA 1 is attached to the Stretcher Unit Z or the Connector Unit A.
  • the Releasable Linker RL is a glycoside.
  • the Releasable Linker RL is wherein Su is a hexose form a monosaccharide; O' represents the oxygen atom of a glycosidic bond that is capable of cleavage by a glycosidase; the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.
  • the Releasable Linker RL is the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.
  • the Spacer Unit Y is wherein EWG is an electron-withdrawing group; and the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
  • the Spacer Unit Y is the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
  • R 17 is C 1 -C 10 alkylene; A is a bond; RL is –AA 1 -AA 2 –; AA 1 and AA 2 are each independently a proteinogenic amino acid; the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
  • A is a bond; .
  • Y-D is the wavy line indicates the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
  • Y-D is the wavy line indicates the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
  • the compound is ,
  • the Ligand-Drug Conjugate compound is a compound of Table 3.
  • p is an integer ranging from 2 to 6.
  • p is 4.
  • the composition comprises a plurlaity of Ligand-Drug Conjugate compounds with an average drug loading from 2 to 8. In some embodiments, the average drug loading is about 4. In some embodiments, the average drug loading is from 3.5 to 4.5.
  • Also provided herein is a method of treating cancer comprising administering a therapeutically effective amount of the Ligand-Drug Conjugate compound of any one of claims 66-96, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • the subject tolerates treatment with the Ligand-Drug Conjugate compound better than treatment with another Ligand-Drug Conjugate compound in therapeutically effective doses.
  • the another Ligand-Drug Conjugate compound comprises a monomethyl auristatin E or monomethyl auristatin F Drug Unit.
  • FIG. 1 Illustrates the in vivo mean tumor volume data for various Ag1 ADCs in the A2058 melanoma xenograft model.
  • FIG 2. Illustrates the in vivo mean tumor volume data for various h2A2 ADCs in the Detroit562 pharyngeal cancer xenograft model.
  • FIG 3. Illustrates the in vivo median tumor volume data for various cAC10 ADCs in the Karpas/KarpasBVR admixed Hodgkin lymphoma xenograft model.
  • FIG 5. Illustrates the in vivo mean tumor volume data for various cAC10 ADCs in the Karpas Hodgkin lymphoma xenograft model.
  • FIG 6. Summarizes plasma neutrophil levels at day 5 and day 8 following administration by non-binding ADCs to rats.
  • FIG 7. Summarizes reticulocyte levels at day 5 and day 8 following administration by non-binding ADCs to rats.
  • FIG 8. Summarizes platelet levels at day 5 and day 8 following administration by non-binding ADCs to rats.
  • FIG 9. Summarizes aspartate transaminase (AST) levels at day 8 following administration by non-binding ADCs to rats.
  • FIG 10. Illustrates the efficacy of a variety of hCR011 ADCs and a non-binding control ADC as measured in the WM2664 melanoma xenograft model.
  • FIG 11. Illustrates the efficacy of a variety of hCR011 ADCs and non-binding control ADCs as measured in the SKMEL5 melanoma xenograft model.
  • FIG 13. Illustrates the efficacy of non-binding, Ag2 and hCR011 ADCs as measured in the PDX_1 melanoma xenograft model.
  • FIG 14. Illustrates the efficacy of non-binding, Ag2 and hCR011 ADCs as measured in the PDX_4 melanoma xenograft model.
  • FIG 14. Illustrates the efficacy of non-binding, Ag2 and hCR011 ADCs as measured in the PDX_3 NSCLC xenograft model.
  • FIG 16. Summarizes the anti-tumor activity of 6 hCR011 ADCs using AUC.3.
  • FIG 17. Summarizes plasma neutrophil levels at baseline, day 4, day 15, and day 29 following administration of hCR011 ADCs to cynomologous monkeys.
  • FIG 18. Summarizes reticulocyte levels at baseline, day 4, day 15, and day 29 following administration of hCR011 ADCs to cynomologous monkeys.
  • FIG 19. Summarizes reticulocyte levels at baseline, day 4, day 15, and day 29 following administration of hCR011 ADCs to cynomologous monkeys.
  • FIG 20 Summarizes aspartate transaminase levels at baseline and day 8 following administration of hCR011 ADCs to cynomologous monkeys.
  • FIG 21 shows neutrophil counts from blood samples taken prior to dosing and post-dose on Day 8. DETAILED DESCRIPTION OF THE INVENTION [0084]
  • One drug class of interest for use in Ligand-Drug Conjguates is auristatins.
  • Auristatins have been shown to be effective payloads in some Ligand-Drug Conjugates (LDCs), but it is believed that their hydrophobicity can contribute to off-target toxicity due to increased permeability and high bystander activity of the free auristatin. Additionally, hydrophobic payloads, such as auristatins, may increase the hydrophobicity of the LDC, resulting in rapid clearance of the LDC from the body of a subject. Therefore, there is a need for auristain conjugates engineered to have optimized cell permeability, pharmacokinetics, and toxicity profile.
  • LDCs Ligand-Drug Conjugates
  • hydrophilic groups of the auristatin compounds provided herein influence the properties of the compounds and of resulting conjugates (e.g., Ligand-Drug Conjugates).
  • the hydrophilic groups are believed to increase the effectiveness of the resulting conjugates in two ways.
  • Conjugates comprising a hydrophilic auristatin group may improve tumor exposure to the Drug Unit due to decreased plasma clearance, and they may simultaneously demonstrate reduced off-target toxicity due to decreased cell permeability of the free drug after it is released from the conjugate.
  • the trade name includes the product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context.
  • all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related.
  • the Concise Dictionary of Biomedicine and Molecular Biology Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 5 th ed., 2013, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, 2 nd ed., 2006, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.
  • the term "about” refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system.
  • reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”.
  • any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • reference to the trade name also refers to the product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context.
  • the term "and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other.
  • the term “and/or” as used in a phrase such as “A and/or B” herein is intended to include “A and B,” “A or B,” “A” (alone), and “B” (alone).
  • the term “and/or” as used in a phrase such as "A, B, and/or C” is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).
  • antibody as used herein is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (i.e., antigen- binding fragments) that retain, at least in part, one or more of the the desired biological activities of the full-length antibody, for example, affinity for its cognate antigen.
  • the native form of an antibody is a tetramer and consists of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain. In each pair, the light and heavy chain variable regions (VL and VH) are together primarily responsible for binding to an antigen.
  • the light chain and heavy chain variable domains consist of a framework region interrupted by three hypervariable regions, also called “complementarity determining regions” or “CDRs.”
  • the constant regions are recognized by and interact with the immune system (see, e.g., Janeway et al., 2001, Immunol. Biology, 5th Ed., Garland Publishing, New York).
  • the antibodies herein are of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or subclass thereof.
  • the antibody is derived from a suitable species.
  • the antibody is of human or murine origin. In some aspects, the antibody is human, humanized, or chimeric. An antibody can be human, humanized, chimeric and/or affinity matured, as well as an antibody from other species, for example, mouse and rabbit, etc.
  • antibody thus includes, for instance, a polypeptide product of B cells within the immunoglobulin class of polypeptides that is able to bind to a specific molecular antigen and is composed of two identical pairs of polypeptide chains, wherein each pair has one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), each amino-terminal portion of each chain includes a variable region of about 100 to about 130 or more amino acids, and each carboxy-terminal portion of each chain includes a constant region. See, e.g., Antibody Engineering (Borrebaeck ed., 2d ed. 1995); and Kuby, Immunology (3d ed. 1997).
  • antibody also includes, but is not limited to, synthetic antibodies, recombinantly produced antibodies, camelized antibodies, intrabodies, anti-idiotypic (anti-Id) antibodies, and functional fragments (e.g., antigen-binding fragments) of any of the above, which refers to a portion of an antibody heavy and/or light chain polypeptide that retains some or all of the binding activity of the antibody from which the fragment was derived.
  • Non-limiting examples of functional fragments include single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments, F(ab’) fragments, F(ab) 2 fragments, F(ab’) 2 fragments, disulfide-linked Fvs (dsFv), Fd fragments, Fv fragments, diabody, triabodies, tetrabodies, and minibodies.
  • antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, for example, antigen-binding domains or molecules that contain an antigen- binding site that binds to an antigen (e.g., one or more CDRs of an antibody).
  • an antigen e.g., one or more CDRs of an antibody.
  • antibody fragments can be found in, for example, Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers ed., 1995); Huston et al., 1993, Cell Biophysics 22:189-224; Plückthun and Skerra, 1989, Meth. Enzymol. 178:497-515; and Day, Advanced Immunochemistry (2d ed. 1990).
  • the antibodies provided herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecule.
  • the term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that are present, in some aspects, in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site.
  • an “intact antibody” is one which comprises an antigen-binding variable region as well as a light chain constant domain (CL) and heavy chain constant domains, CH1, CH 2 , CH 3 , and CH4, as appropriate for the antibody class.
  • the constant domains are native sequence constant domains (e.g., human native sequence constant domains) and in other aspects are amino acid sequence variants thereof.
  • An “antibody fragment” comprises a portion of an intact antibody, comprising the antigen-binding or variable region thereof.
  • antibody fragments include Fab, Fab’, F(ab’) 2 , and Fv fragments, diabodies, triabodies, tetrabodies, linear antibodies, single- chain antibody molecules, scFv, scFv-Fc, multispecific antibody fragments formed from antibody fragment(s), a fragment(s) produced by a Fab expression library, or an epitope- binding fragments of any of the above which immunospecifically bind to a target antigen (e.g., a cancer cell antigen, a viral antigen or a microbial antigen).
  • a target antigen e.g., a cancer cell antigen, a viral antigen or a microbial antigen.
  • an “antigen-binding fragment” (or simply “fragment”) or "antigen-binding domain", of an antigen binding protein (e.g., an antibody) as used herein refers to one or more fragments of an antigen binding protein (e.g., an antibody), regardless of how obtained or synthesized, that retain the ability to specifically bind to the antigen bound by the whole antigen binding protein.
  • antibody fragments include, but are not limited to, Fv; Fab; Fab'; Fab’-SH; F(ab') 2 ; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments.
  • a “Fv” fragment includes a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain.
  • a “Fab” fragment includes, the constant domain of the light chain and the first constant domain (CH1) of the heavy chain, in addition to the heavy and light chain variable domains of the Fv fragment.
  • a “F(ab') 2 ” fragment includes two Fab fragments joined, near the hinge region, by disulfide bonds.
  • An “antigen” is an entity to which an antibody specifically binds.
  • the terms “specific binding” and “specifically binds” mean that the antibody or antibody derivative will bind, in a highly selective manner, with its corresponding epitope of a target antigen and not with the multitude of other antigens.
  • the antibody or antibody derivative binds with an affinity of at least about 1x10 -7 M, and preferably 10 -8 M to 10 -9 M, 10 -10 M, 10 -11 M, or 10 -12 M and binds to the predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen.
  • a non-specific antigen e.g., BSA, casein
  • the term “inhibits” or “inhibition of” means to reduce by a measurable amount, or to prevent entirely.
  • the term “therapeutically effective amount” refers to an amount of a conjugate effective to treat a disease or disorder in a mammal.
  • the therapeutically effective amount of the conjugate may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer.
  • the drug inhibits growth and/or kills existing cancer cell.
  • the drug is cytostatic and/or cytotoxic.
  • efficacy is measured by commonly available tools.
  • efficacy is measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR).
  • Percent (%) amino acid sequence identity and “homology” with respect to a peptide, polypeptide or antigen binding protein (e.g., antibody) sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN TM (DNASTAR) software.
  • the % sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B is calculated as follows: 100 times the fraction X/Y where X is the number of amino acid residues scored as identical matches by the sequence in that program's alignment of A and B, and where Y is the total number of amino acid residues in B.
  • % amino acid sequence identity values used herein are calculated according to this formula using the ALIGN-2 computer program. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % sequence identity of A to B will not equal the % sequence identity of B to A.
  • the term “substantial” or “substantially” refers to a majority, i.e. >50% of a population, of a mixture or a sample, preferably more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, or 99% of a population.
  • cytotoxic activity refers to a cell-killing effect of a drug or Ligand- Drug Conjugate compound or an intracellular metabolite of a Ligand-Drug Conjugate compound. In some aspects, cytotoxic activity is expressed as the IC 50 value, which is the concentration (molar or mass) per unit volume at which half the cells survive.
  • cytostatic activity refers to an anti-proliferative effect of a drug or Ligand-Drug Conjugate compound or an intracellular metabolite of a Ligand-Drug Conjugate compound.
  • cytotoxic agent as used herein refers to a substance that has cytotoxic activity and causes destruction of cells.
  • cytostatic agent refers to a substance that inhibits a function of cells, including cell growth or multiplication. Cytostatic agents include inhibitors such as protein inhibitors, e.g., enzyme inhibitors. Cytostatic agents have cytostatic activity.
  • cancer and “cancerous” refer to or describe the physiological condition or disorder in mammals that is typically characterized by unregulated cell growth. A “tumor” comprises one or more cancerous cells.
  • immunoglobulin refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light (L) low molecular weight chains and one pair of heavy (H) chains, all four inter-connected by disulfide bonds.
  • L light
  • H heavy
  • each heavy chain typically is comprised of a heavy chain variable region (abbreviated herein as V H or VH) and a heavy chain constant region (C H or CH).
  • the heavy chain constant region typically is comprised of three domains, CH1, CH 2 , and CH 3 .
  • the heavy chains are generally inter- connected via disulfide bonds in the so-called “hinge region.”
  • Each light chain typically is comprised of a light chain variable region (abbreviated herein as VL or VL) and a light chain constant region (CL or CL).
  • the light chain constant region typically is comprised of one domain, C L .
  • the CL can be of ⁇ (kappa) or ⁇ (lambda) isotype.
  • the terms “constant domain” and “constant region” are used interchangeably herein.
  • An immunoglobulin can derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG, and IgM.
  • IgG subclasses are also well known to those in the art and include but are not limited to human IgG1, IgG2, IgG3 and IgG4.
  • "Isotype” refers to the antibody class or subclass (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes.
  • HVR hypervariable region
  • HVRs can form structurally defined loops (“hypervariable loops”).
  • native four-chain antibodies comprise six HVRs; three in the VH (H1, H2, H3), and three in the VL (L1, L2, L3).
  • H3 and L3 display the most diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu, in Methods in Molecular Biology 248:1 -25 (Lo, ed., Human Press, Totowa, NJ, 2003). Indeed, naturally-occurring camelid antibodies consisting of a heavy chain only are functional and stable in the absence of light chain.
  • HVRs generally comprise amino acid residues from the hypervariable loops and/or from the “complementary determining regions” (CDRs), CDRs being of highest sequence variability and/or involved in antigen recognition.
  • CDRs complementary determining regions
  • a variety of schemes for defining the boundaries of a given CDR are known in the art. For example, the Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et at., Sequences of Proteins of Immunological Interest, 5th Ed.
  • Chothia refers instead to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)).
  • the AbM CDRs represent a compromise between the Kabat CDRs and Chothia structural loops and are used by Oxford Molecular’s AbM antibody modeling software.
  • the “contact” CDRs are based on an analysis of the available complex crystal structures. Additional details on the foregoing schemes as well as other numbering conventions are provided in the following references: Al-Lazikani et al., (1997) J. Mol. Biol.
  • HVR regions and associated sequences are the same as the CDR regions and associated sequences based upon one of the foregoing numbering conventions.
  • HVRs can comprise extended HVRs as follows: 24-36 or 24-34 (L1 ), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 (H1 ), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH.
  • the variable domain residues are numbered according to Kabat et at., supra, for each of these definitions.
  • CDR complementary determining region
  • individual CDRs e.g., "CDR-H1, CDR-H2
  • CDR-H1, CDR-H2 individual CDRs
  • the scheme for identification of a particular CDR or CDRs is specified, such as the CDR as defined by the IMGT, Kabat, AbM, Chothia, or Contact method.
  • the particular amino acid sequence of a CDR is given.
  • the antigen binding protein comprises CDRs and/or HVRs as defined by the IMGT system.
  • the antigen binding protein comprises CDRs or HVRs as defined by the Kabat system.
  • the antigen binding protein comprises CDRs or HVRs as defined by the AbM system.
  • the antigen binding protein comprises CDRs or HVRs as defined by the Chothia system.
  • the antigen binding protein comprises CDRs or HVRs as defined by the IMGT system.
  • variable region refers to the domain of an antigen binding protein (e.g., an antibody) heavy or light chain that is involved in binding the antigen binding protein (e.g., antibody) to antigen.
  • the variable regions or domains of the heavy chain and light chain (VH and VL, respectively) of an antigen binding protein such as an antibody can be further subdivided into regions of hypervariability (or hypervariable regions, which may be hypervariable in sequence and/or form of structurally defined loops), such as hypervariable regions (HVRs) or complementarity-determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs).
  • HVRs hypervariable regions
  • CDRs complementarity-determining regions
  • HVR-H1, HVR-H2, HVR-H3 there are three HVRs (HVR-H1, HVR-H2, HVR-H3) or CDRs (CDR-H1, CDR-H2, CDR-H3) in each heavy chain variable region, and three HVRs (HVR-L1, HVR-L2, HVR- L3) or CDRs in (CDR-L1, CDR-L2, CDR-L3) in each light chain variable region.
  • HVR-L1, HVR-L2, HVR- L3 three HVRs (HVR-L1, HVR-L2, HVR- L3) or CDRs in (CDR-L1, CDR-L2, CDR-L3) in each light chain variable region.
  • “Framework regions” and “FR” are known in the art to refer to the non-HVR or non-CDR portions of the variable regions of the heavy and light chains.
  • each full-length heavy chain variable region FR-H1, FR-H2, FR-H3, and FR-H4
  • four FRs in each full-length light chain variable region FR-L1, FR-L2, FR-L3, and FR-L4
  • three HVRs or CDRs and four FRs are typically arranged from amino-terminus to carboxy-terminus in the following order: FR1, HVR1, FR2, HVR2, FR3, HVR3, FR4 in the case of HVRs, or FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 in the case of CDRs (See also Chothia and Lesk J. Mot.
  • VH or VL domain can be sufficient to confer antigen-binding specificity.
  • antibodies that bind a particular antigen can be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al. J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).
  • heavy chain variable region refers to a region comprising heavy chain HVR-H1, FR-H2, HVR-H2, FR-H3, and HVR-H3.
  • a heavy chain variable region may comprise heavy chain CDR-H1, FR-H2, CDR-H2, FR-H3, and CDR-H3.
  • a heavy chain variable region also comprises at least a portion of an FR-H1 and/or at least a portion of an FR-H4.
  • the term “heavy chain constant region” as used herein refers to a region comprising at least three heavy chain constant domains, C H 1, C H 2, and C H 3.
  • Nonlimiting exemplary heavy chain constant regions include ⁇ , ⁇ , and ⁇ .
  • Nonlimiting exemplary heavy chain constant regions also include ⁇ and ⁇ .
  • Each heavy constant region corresponds to an antibody isotype.
  • an antibody comprising a ⁇ constant region is an IgG antibody
  • an antibody comprising a ⁇ constant region is an IgD antibody
  • an antibody comprising an ⁇ constant region is an IgA antibody
  • an antibody comprising a ⁇ constant region is an IgM antibody
  • an antibody comprising an ⁇ constant region is an IgE antibody.
  • IgG antibodies include, but are not limited to, IgG1 (comprising a ⁇ 1 constant region), IgG2 (comprising a ⁇ 2 constant region), IgG3 (comprising a ⁇ 3 constant region), and IgG4 (comprising a ⁇ 4 constant region) antibodies;
  • IgA antibodies include, but are not limited to, IgA1 (comprising an ⁇ 1 constant region) and IgA2 (comprising an ⁇ 2 constant region) antibodies; and IgM antibodies include, but are not limited to, IgM1 and IgM2.
  • HC heavy chain
  • full- length heavy chain refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence.
  • VL light chain variable region
  • the light chain variable region comprises light chain CDR-L1, FR-L2, CDR- L2, FR-L3, and CDR-L3. In some embodiments, a light chain variable region also comprises an FR-L1 and/or an FR-L4.
  • the term “light chain constant region” as used herein refers to a region comprising a light chain constant domain, CL. Nonlimiting exemplary light chain constant regions include ⁇ and ⁇ .
  • the term “light chain” (LC) as used herein refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region.
  • full-length light chain refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence.
  • the "EU numbering system” or "EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991).
  • the "EU index as in Kabat” refers to the residue numbering of the human IgG1 EU antibody. Unless stated otherwise herein, references to residue numbers in the constant domain of antibodies means residue numbering by the EU numbering system.
  • derivative refers to a molecule (e.g., an antigen binding protein such as an antibody or fragment thereof) that includes a chemical modification other than an insertion, deletion, or substitution of amino acids (or nucleic acids).
  • derivatives comprise covalent modifications, including, but not limited to, chemical bonding with polymers, lipids, or other organic or inorganic moieties.
  • a derivative of a particular antigen binding protein can have a greater circulating half-life than an antigen binding protein that is not chemically modified.
  • a derivative can have improved targeting capacity for desired cells, tissues, and/or organs.
  • a derivative of an antigen binding protein is covalently modified to include one or more polymers, including, but not limited to, monomethoxy-polyethylene glycol, dextran, cellulose, or other carbohydrate based polymers, poly-(N-vinyl pyrrolidone)- polyethylene glycol, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, as well as mixtures of such polymers. See, e.g., U.S. Pat. Nos.
  • antigen binding proteins e.g., antibodies or fragments thereof
  • competition when used in the context of antigen binding proteins (e.g., antibodies or fragments thereof) that compete for the same epitope means competition between antigen binding proteins as determined by an assay in which the antigen binding protein (e.g., an antibody or fragment thereof) being tested (e.g., a test antibody) prevents or inhibits (partially or completely) specific binding of a reference antigen binding protein (e.g., a reference antibody) to a common antigen (e.g., gpNMB or a fragment thereof).
  • a reference antigen binding protein e.g., a reference antibody
  • SPR surface plasmon resonance
  • RIA solid phase direct or indirect radioimmunoassay
  • EIA solid phase direct or indirect enzyme immunoassay
  • sandwich competition assay see, e.g., Stahli et al., 1983, Methods in Enzymology 9:242- 253
  • solid phase direct biotin-avidin EIA see, e.g., Kirkland et al., 1986, J. Immunol.
  • solid phase direct labeled assay solid phase direct labeled sandwich assay (see, e.g., Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid phase direct label RIA using I-125 label (see, e.g., Morel et al., 1988, Mol. Immunol. 25:7-15); solid phase direct biotin-avidin EIA (see, e.g., Cheung, et al., 1990, Virology 176:546-552); direct labeled RIA (Moldenhauer et al., 1990, Scand. J. Immunol. 32:77-82).
  • the test antigen binding protein is present in excess (e.g., at least 2x, 5x, 10x, 20x or 100x).
  • a competing antigen binding protein is present in excess, it will inhibit specific binding of a reference antigen binding protein to a common antigen by at least 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%.
  • each antigen binding protein e.g., an antibody or fragment thereof
  • detectably inhibits the binding of the other antigen binding protein with its cognate epitope whether to the same, greater, or lesser extent
  • the antigen binding proteins are said to “cross-compete” with each other for binding of their respective epitope(s) or to ”cross-block” one another.
  • an “affinity matured” antibody refers to an antibody with one or more alterations in one or more hypervariable regions (HVRs) compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen.
  • an affinity matured antibody refers to an antibody with one or more alterations in one or more complementarity determining regions (CDRs) compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen.
  • the term “specifically binds”, “binding” or simply “binds” or other related terms in the context of the binding of an antigen binding protein to its target antigen means that the antigen binding protein exhibits essentially background binding to non- target molecules.
  • An antigen binding protein that specifically binds a target antigen e.g., gpNMB
  • KD KD
  • M refers to the dissociation equilibrium constant of a particular antigen binding protein-antigen interaction (e.g., antibody-antigen interaction).
  • Affinity as used herein, and KD are inversely related, such that higher affinity is intended to refer to lower KD, and lower affinity is intended to refer to higher KD.
  • An “antibody-drug-conjugate” or simply “ADC” refers to an antibody conjugated to a cytotoxic agent or cytostatic agent.
  • An antibody-drug-conjugate typically binds to the target antigen (e.g., gpNMB) on a cell surface followed by internalization of the antibody- drug-conjugate into the cell where the drug is released.
  • a “cytotoxic effect” refers to the depletion, elimination and/or killing of a target cell.
  • a “cytotoxic agent” refers to an agent that has a cytotoxic effect on a cell.
  • a “cytostatic effect” refers to the inhibition of cell proliferation.
  • a “cytostatic agent” refers to an agent that has a cytostatic effect on a cell, thereby inhibiting the growth of and/or expansion of a specific subset of cells. Cytostatic agents can be conjugated to an antibody or administered in combination with an antibody.
  • the term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions.
  • a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain.
  • the C-terminal lysine (Lys447) of the Fc region may or may not be present.
  • numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991. [0137]
  • a “functional Fc region” possesses an “effector function” of a native sequence Fc region.
  • effector functions include Fc receptor binding; C1q binding; complement dependent cytotoxicity (CDC); antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cellular phagocytosis (ADCP); down regulation of cell surface receptors (e.g. B cell receptor; BCR), etc.
  • CDC complement dependent cytotoxicity
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • BCR B cell receptor
  • effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays.
  • a “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature.
  • Native sequence human Fc regions include a native sequence human IgG1 Fc region (non-A and A allotypes); native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof.
  • a “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification.
  • Fc receptor or “FcR” describes a receptor that binds to the Fc region of an antibody.
  • an Fc ⁇ R is a native human FcR.
  • an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII subclasses, including allelic variants and alternatively spliced forms of those receptors.
  • Fc ⁇ RII receptors include Fc ⁇ RIIA (an “activating receptor”) and Fc ⁇ RIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof.
  • Activating receptor Fc ⁇ RIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain
  • Inhibiting receptor Fc ⁇ RIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain.
  • ITAM immunoreceptor tyrosine-based activation motif
  • ITIM immunoreceptor tyrosine-based inhibition motif
  • FcR Fc receptor
  • FcRn neonatal receptor
  • Methods of measuring binding to FcRn are known (see, e.g., Ghetie and Ward., Immunol.
  • “Effector functions” refer to biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cellular phagocytosis (ADCP); down regulation of cell surface receptors (e.g. B cell receptor); and B cell activation.
  • CDC complement dependent cytotoxicity
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • ADCP antibody-dependent cellular phagocytosis
  • Such functions can be affected by, for example, binding of an Fc effector domain(s) to an Fc receptor on an immune cell with phagocytic or lytic activity or by binding of an Fc effector domain(s) to components of the complement system.
  • the effect(s) mediated by the Fc-binding cells or complement components result in inhibition and/or depletion of the CD33 targeted cell.
  • Fc regions of antibodies can recruit Fc receptor (FcR)- expressing cells and juxtapose them with antibody-coated target cells.
  • Cells expressing surface FcR for IgGs including Fc ⁇ RIII (CD16), Fc ⁇ RII (CD32) and Fc ⁇ RIII (CD64) can act as effector cells for the destruction of IgG-coated cells.
  • Such effector cells include monocytes, macrophages, natural killer (NK) cells, neutrophils and eosinophils. Engagement of Fc ⁇ R by IgG activates antibody-dependent cellular cytotoxicity (ADCC) or antibody- dependent cellular phagocytosis (ADCP). ADCC is mediated by CD16 + effector cells through the secretion of membrane pore-forming proteins and proteases, while phagocytosis is mediated by CD32 + and CD64 + effector cells (see, e.g., Fundamental Immunology, 4 th ed., Paul ed., Lippincott-Raven, N.Y., 1997, Chapters 3, 17 and 30; Uchida et al., 2004, J. Exp. Med.
  • Human effector cells are leukocytes which express one or more FcRs and perform effector functions. In certain embodiments, the cells express at least Fc ⁇ RIII and perform ADCC effector function(s). Examples of human leukocytes which mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer (NK) cells, monocytes, cytotoxic T cells, and neutrophils.
  • PBMC peripheral blood mononuclear cells
  • NK natural killer cells
  • monocytes cytotoxic T cells
  • neutrophils The effector cells may be isolated from a native source, e.g., from blood.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • FcRs Fc receptors
  • cytotoxic effector cells e.g. NK cells, neutrophils, and macrophages.
  • NK cells express Fc ⁇ RIII only, whereas monocytes express Fc ⁇ RI, Fc ⁇ RII, and Fc ⁇ RIII.
  • FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu.
  • ADCC activity of a molecule of interest can be assessed in vitro, such as that described in US Pat. Nos. 5,500,362 or 5,821,337 or U.S. Pat. No. 6,737,056 (Presta), can be performed.
  • Useful effector cells for such assays include PBMC and NK cells.
  • ADCC activity of the molecule of interest can also be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. (USA) 95:652-656 (1998).
  • “Complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to the Fc region of antibodies (of the appropriate subclass), which are bound to their cognate antigen on a target cell. This binding activates a series of enzymatic reactions culminating in the formation of holes in the target cell membrane and subsequent cell death.
  • complement Activation of complement may also result in deposition of complement components on the target cell surface that facilitate ADCC by binding complement receptors (e.g., CR3) on leukocytes.
  • complement receptors e.g., CR3
  • a CDC assay e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), can be performed.
  • Polypeptide variants with altered Fc region amino acid sequences polypeptides such as an antibody with a variant Fc region
  • increased or decreased C1q binding capability are described, e.g., in U.S. Pat. No. 6,194,551 B1, U.S. Pat. No. 7,923,538, U.S. Pat. No.
  • ADCP antibody-dependent cellular phagocytosis
  • phagocytic immune cells e.g., macrophages, neutrophils and dendritic cells
  • a polypeptide variant with “altered” FcR binding affinity or ADCC activity is one which has either enhanced or diminished FcR binding activity and/or ADCC activity compared to a parent polypeptide or to a polypeptide comprising a native sequence Fc region.
  • the polypeptide variant which “displays increased binding” to an FcR binds at least one FcR with better affinity than the parent polypeptide.
  • the polypeptide variant which “displays decreased binding” to an FcR binds at least one FcR with lower affinity than a parent polypeptide.
  • such variants which display decreased binding to an FcR may possess little or no appreciable binding to an FcR, e.g., 0- 20% binding to the FcR compared to a native sequence IgG Fc region.
  • the term “substantially similar” or “substantially the same,” as used herein, denotes a sufficiently high degree of similarity between two or more numeric values such that one of skill in the art would consider the difference between the two or more values to be of little or no biological and/or statistical significance within the context of the biological characteristic measured by said value. In some embodiments the two or more substantially similar values differ by no more than about any one of 5%, 10%, 15%, 20%, 25%, or 50%.
  • Affinity refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen).
  • the affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein.
  • An “autoimmune disease” as used herein refers to a disease or disorder arising from and directed against an individual’s own tissues or proteins.
  • Principal as used herein refers to a subject to whom is administered a Ligand- Drug Conjugate compound of the present invention.
  • Patient includes, but are not limited to, a human, rat, mouse, guinea pig, non-human primate, pig, goat, cow, horse, dog, cat, bird and fowl.
  • the patient is a rat, mouse, dog, human or non-human primate, more typically a human.
  • the terms “treat” or “treatment,” unless otherwise indicated by context, refer to therapeutic treatment and prophylactic wherein the object is to inhibit or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder.
  • the term “treating” includes any or all of: killing tumor cells; inhibiting growth of tumor cells, cancer cells, or of a tumor; inhibiting replication of tumor cells or cancer cells, lessening of overall tumor burden or decreasing the number of cancerous cells, and ameliorating one or more symptoms associated with the disease.
  • the term “treating” includes any or all of: inhibiting replication of cells associated with an autoimmune disease state including, but not limited to, cells that produce an autoimmune antibody, lessening the autoimmune- antibody burden and ameliorating one or more symptoms of an autoimmune disease.
  • Compound refers to and encompasses the chemical compound itself, either named or represented by structure, and salt form(s) thereof, whether explicitly stated or not, unless context makes clear that such salt forms are to be excluded.
  • the term “compound” further encompasses solvate forms of the compound, in which solvent is noncovalently associated with the compound or is reversibly associated covalently with the compound, as when a carbonyl group of the compound is hydrated to form a gem-diol.
  • Solvate forms include those of the compound itself and its salt form(s) and are inclusive of hemisolvates, monosolvates, disolvates, including hydrates; when a compound is associated with two or more solvent molecules, the two or more solvent molecules are the same or different.
  • a compound of the invention will include an explicit reference to one or more of the above forms, e.g., salts and solvates, which does not imply any solid state form of the compound; however, this reference is for emphasis only, and is not to be construed as excluding any other of the forms as identified above.
  • salt and/or solvate form of a compound or a Ligand Drug Conjugate composition when explicit reference to a salt and/or solvate form of a compound or a Ligand Drug Conjugate composition is not made, that omission is not to be construed as excluding the salt and/or solvate form(s) of the compound or Conjugate unless context make clear that such salt and/or solvate forms are to be excluded.
  • a salt form of a compound is of one or more internal salt forms and/or involves the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion.
  • the counterion in a salt form of a compound is typically an organic or inorganic moiety that stabilizes the charge on the parent compound.
  • a salt form of a compound has one or more than one charged atom in its structure. In instances where multiple charged atoms are part of the salt form, multiple counter ions and/or multiple charged counter ions are present.
  • a salt form of a compound typically has one or more charged atoms corresponding to those of the non-salt form of the compound and one or more counterions.
  • the non- salt form of a compound contains at least one amino group or other basic moeity, and accordingly in the presence of an acid, an acid addition salt with the basic moiety is obtained.
  • the non-salt form of a compound contains at least one carboxylic acid group or other acidic moiety, and accordingly in the presence of a base, a carboxylate or other anionic moiety is obtained.
  • Exemplary salts include, but are not limited to, sulfate, trifluoroacetate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1’-methylene-bis- (2-hydroxy-3-naphthoate)) salts.
  • pamoate i.e., 1,1’-m
  • a pharmaceutically acceptable salt is a salt form of a compound that is suitable for administration to a subject as described herein and in some aspects includes countercations or counteranions as described by P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich:Wiley-VCH/VHCA, 2002.
  • a “Linker Unit” as used herein is a bifunctional moiety that connects or is capable of connecting a Drug Unit to a Ligand Unit in a Ligand-Drug Conjugate compound.
  • the Linker Units of the present invention comprise two or more components selected from the group consisting of a Stretcher Unit which in some embodiments will have a Basic Unit; a Connector Unit; a Parallel Connector Unit; a Releasable Linker; and a Spacer Unit.
  • a Stretcher Unit which in some embodiments will have a Basic Unit; a Connector Unit; a Parallel Connector Unit; a Releasable Linker; and a Spacer Unit.
  • “PEG”, “PEG Unit” or “polyethylene glycol” as used herein is an organic moiety comprising repeating ethylene-oxy subunits and is polydisperse, monodisperse, or discrete (i.e., having discrete number of ethylene-oxy subunits).
  • Polydisperse PEGs are a heterogeneous mixture of sizes and molecular weights whereas monodisperse PEGs are typically purified from heterogeneous mixtures and are therefore provide a single chain length and molecular weight.
  • Preferred PEG Units are discrete PEGs, compounds that are synthesized in stepwise fashion and not via a polymerization process. Discrete PEGs provide a single molecule with defined and specified chain length.
  • the PEG Unit provided herein comprises one or multiple polyethylene glycol chains, each comprising one or more ethyleneoxy subunits, covalently attached to each other. The polyethylene glycol chains are linked together in any pattern (e.g., in a linear, branched, or star shaped configuration).
  • At least one of the polyethylene glycol chains prior to incorporation into a Ligand-Drug Conjugate compound is derivitized at one end with an alkyl moiety substituted with an electrophilic group for covalent attachment to the carbamate nitrogen of a methylene carbamate unit (i.e., represents an instance of R).
  • the terminal ethyleneoxy subunit in each polyethylene glycol chains not involved in covalent attachment to the remainder of the Linker Unit is modified with a PEG Capping Unit, typically H or an optionally substituted alkyl such as –CH 3 , -CH 2 CH 3 or -CH 2 CH 2 CO 2 H.
  • a preferred PEG Unit has a single polyethylene glycol chain with 4 to 24 –CH 2 CH 2 O- subunits covalently attached in series and terminated at one end with a PEG Capping Unit.
  • Halogen as the term is used herein by itself or in combination with another term, unless otherwise stated or implied by context, refers to fluorine, chlorine, bromine or iodine and is typically -F or -Cl.
  • alkyl by itself or as part of another term refers to a straight chain or branched, saturated hydrocarbon having the indicated number of carbon atoms (e.g., “-C 1 -C 4 alkyl,” “-C 1 -C 8 alkyl,” or “-C 1 -C 10 ” alkyl refer to an alkyl group having from 1 to 4, 1 to 8, or 1 to 10 carbon atoms, respectively). When the number of carbon atoms is not indicated, the alkyl group has from 1 to 8 carbon atoms.
  • Representative straight chain “-C 1 -C 8 alkyl” groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl and -n-octyl; while branched –C 3 -C 8 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and -2- methylbutyl.
  • alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of the stated number of carbon atoms, typically 1-4, 1-8, or 1-10 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • Typical alkylene radicals include, but are not limited to: methylene (-CH 2 -), 1,2-ethylene (-CH 2 CH 2 -), 1,3-propylene (-CH 2 CH 2 CH 2 -), 1,4-butylene (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • an alkylene is a branched or straight chain hydrocarbon (i.e., it is not a cyclic hydrocarbon).
  • An alkenyl moiety, group or substituent having multiple double bonds may have the double bonds arranged contiguously (i.e., a 1,3-butadienyl moiety) or non- contiguously with one or more intervening saturated carbon atoms or a combination thereof, provided that a cyclic, contiguous arrangement of double bonds do not form a cyclic conjugated system of 4n + 2 electrons (i.e., is not aromatic).
  • An alkenyl moiety, group or substituent contains at least one sp 2 carbon atom in which that carbon atom is divalent and is doubly bonded to another organic moiety or Markush structure to which it is associated, or contains at least two sp 2 carbon atoms in conjugation to each other in which one of the sp 2 carbon atoms is monovalent and is singly bonded to another organic moiety or Markush structure to which it is associated.
  • alkenyl is used as a Markush group (i.e., is a substituent) the alkenyl is singly bonded to a Markush formula or another organic moiety with which it is associated through a sp 2 carbon of an alkene functional group of the alkenyl moiety.
  • species encompasses those corresponding to any of the optionally substituted alkyl or carbocyclyl, groups moieties or substituents described herein that has one or more endo double bonds in which a sp 2 carbon atom thereof is monovalent and monovalent moieties derived from removal of a hydrogen atom from a sp 2 carbon of a parent alkene compound.
  • alkenyl encompasses those and/or other linear, cyclic and branched chained, all carbon-containing moieties containing at least one double bond functional group in which one of the sp 2 carbon atoms is monovalent.
  • the number of carbon atoms in an alkenyl moiety is defined by the number of sp 2 carbon atoms of the alkene functional group(s) that defines it as an alkenyl substituent and the total number of contiguous non-aromatic carbon atoms appended to each of these sp 2 carbons not including any carbon atom of the other moiety or Markush structure for which the alkenyl moiety is a variable group and carbon atoms from any optional substituent to the alkenyl moiety. That number ranges from 1 to 50 or 1 to 30, typically 1 to 20 or 1 to 12, more typically, 1 to 8, 1 to 6 or 1 to 4 carbon atoms when the double bond functional group is doubly bonded to a Markush structure (e.g.
  • C2-C 8 alkenyl or C2-C 8 alkenyl means an alkenyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms in which at least two are sp 2 carbon atoms in conjugation with each other with one of these carbon atoms being monovalent
  • C 2 -C 6 alkenyl or C2-C6 alkenyl means an alkenyl moiety containing 2, 3, 4, 5 or 6 carbon atoms in which at least two are sp 2 carbons that are in conjugation with each other with one of these carbon atoms being monovalent.
  • an alkenyl substituent or group is a C2-C6 or C2-C4 alkenyl moiety having only two sp 2 carbons that are in conjugation with each other with one of these carbon atoms being monovalent.
  • an alkenyl substituent is a C2-C6 or C2-C4 alkenyl moiety having only two sp 2 carbons that are in conjugation with each other.
  • an alkenyl moiety has from 2 to 8 carbon atoms.
  • Alkenylene as the term is used herein, by itself of as part of another term, unless otherwise stated or implied by context, refers to an organic moiety, substituent or group that comprises one or more double bond moieties, as previously described for alkenyl, of the stated number of carbon atoms and has two radical centers derived by the removal of two hydrogen atoms from the same or two different sp 2 carbon atoms of an alkene functional group or removal of two hydrogen atoms from two separate alkene functional groups in a parent alkene.
  • an alkenylene moiety is that of an alkenyl radical as described herein in which a hydrogen atom has been removed from the same or different sp 2 carbon atom of a double bond functional group of the alkenyl radical, or from a sp 2 carbon from a different double bonded moiety to provide a diradical.
  • the number of carbon atoms in an alkenylene moiety is defined by the number of sp 2 carbon atoms of its alkene functional group(s) that defines it as an alkenylene moiety and the total number of contiguous non-aromatic carbon atoms appended to each of its sp 2 carbons not including any carbon atoms of the other moiety or Markush structure in which the alkenyl moiety is a present as a variable group. That number, unless otherwise specified, ranges from 2 to 50 or 2 to 30, typically from 2 to 20 or 2 to 12, more typically from 2 to 8, 2 to 6 or 2 to 4 carbon atoms.
  • C2-C 8 alkenylene or C2-C 8 alkenylene means an alkenylene moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms, in which at least two are sp 2 carbons in which one is divalent or both are monovalent, that are in conjugation with each other and
  • C2-C6 alkenylene or C2-C6 alkenylene means an alkenyl moiety containing 2, 3, 4, 5 or 6 carbon atoms in which at least two are sp 2 carbons, in which at least two are sp 2 carbons in which one is divalent or both are monovalent, that are in conjugation with each other.
  • an alkenylene moiety is a C2-C6 or C2-C4 alkenylene having two sp 2 carbons that are in conjugation with each other in which both sp 2 carbon atoms are monovalent. When the number of carbon atoms is not indicated, an alkenylene moiety has from 2 to 8 carbon atoms.
  • Alkynyl as the term is used herein, by itself or as part of another term, unless otherwise stated or implied by context, refers to an organic moiety, substituent or group that comprises one or more triple bond functional groups (e.g., a -C ⁇ C- moiety) or 1, 2, 3, 4, 5, or 6 or more, typically 1, 2, or 3 of such functional groups, more typically one such functional group.
  • An alkynyl moiety, group or substituent having multiple triple bonds may have the triple bonds arranged contiguously or non-contiguously with one or more intervening saturated or unsaturated carbon atoms or a combination thereof, provided that a cyclic, contiguous arrangement of triple bonds do not form a cyclic conjugated system of 4n + 2 electrons (i.e., is not aromatic).
  • An alkynyl moiety, group or substituent contains at least two sp carbon atom in which the carbon atoms are conjugation to each other and in which one of the sp carbon atoms is singly bonded, to another organic moiety or Markush structure to which it is associated.
  • alkynyl When alkynyl is used as a Markush group (i.e., is a substituent) the alkynyl is singly bonded to a Markush formula or another organic moiety with which it is associated through a triple-bonded carbon (i.e., a sp carbon) of a terminal alkyne functional group.
  • species encompasses are any of the alkyl or carbocyclyl, groups moieties or substituents described herein that has one or more endo triple bonds and monovalent moieties derived from removal of a hydrogen atom from a sp carbon of a parent alkyne compound.
  • Such monovalent moieties are exemplified without limitation by -C ⁇ CH, and -C ⁇ C-CH 3 , and -C ⁇ C-Ph.
  • the number of carbon atoms in an alkynyl substituent is defined by the number of sp carbon atoms of the alkene functional group that defines it as an alkynyl substituent and the total number of contiguous non-aromatic carbon atoms appended to each of these sp carbons not including any carbon atom of the other moiety or Markush structure for which the alkenyl moiety is a variable group.
  • That number can vary ranging from 2 to 50, typically 2 to 30, 2 to 20, or 2 to 12, more typically 2 to 8, 2 to 6, or 2 to 4 carbon atoms, when the triple bond functional group is singly bonded to the Markush structure (e.g., -CH ⁇ CH).
  • C2-C 8 alkynyl or C2-C 8 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms in which at least two are sp carbon atoms in conjugation with each other with one of these carbon atoms being monovalent
  • C2-C6 alkynyl or C2-C6 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, or 6 carbon atoms in which at least two are sp carbons that are in conjugation with each other with one of these carbon atoms being monovalent.
  • an alkynyl substituent or group is a C 2 -C 6 or C 2 -C 4 alkynyl moiety having two sp carbons that are in conjugation with each other with one of these carbon atoms being monovalent. When the number of carbon atoms is not indicated, an alkynyl moiety, group or substituent has from 2 to 8 carbon atoms.
  • the term “Prodrug” as used herein refers to a less biologically active or inactive compound which is transformed within the body into a more biologically active compound via a chemical or biological process (i.e., a chemical reaction or an enzymatic biotransformation).
  • a biologically active compound is rendered less biologically active (i.e., is converted to a prodrug) by chemically modifying the compound with a prodrug moiety.
  • the prodrug is a Type II prodrug, which are bioactivated outside cells, e.g., in digestive fluids, or in the body's circulation system, e.g., in blood.
  • Exemplary prodrugs are esters and ⁇ -D-glucopyranosides.
  • aryl by itself or as part of another term, means amonovalent carbocyclic aromatic hydrocarbon radical of the stated number of carbon atoms, typically 6-20 carbon atoms, derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Some aryl groups are represented in the exemplary structures as “Ar”.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like.
  • An exemplary aryl group is a phenyl group.
  • an “arylene,” by itself or as part of another term, is an aryl group as defined above which has two covalent bonds (i.e., it is divalent) and is in the ortho, meta, or para orientations as shown in the following structures, with phenyl as the exemplary group:
  • a “C 3 -C 8 heterocycle,” by itself or as part of another term refers to a monovalentaromatic or non-aromatic monocyclic or bicyclic ring system having from 3 to 8 carbon atoms (also referred to as ring members) and one to four heteroatom ring members independently selected from N, O, P or S, and derived by removal of one hydrogen atom from a ring atom of a parent ring system.
  • one or more N, C or S atoms in the heterocycle is/are oxidized.
  • the ring that includes the heteroatom is aromatic or nonaromatic.
  • Heterocycles in which all the ring atoms are involved in aromaticity are referred to as heteroaryls and otherwise are referred to heterocarbocycles.
  • the heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
  • a heteroaryl is bonded through an aromatic carbon of its aromatic ring system, referred to as a C-linked heteroaryl.
  • nitrogen-containing heterocycles are C-linked or N-linked and include pyrrole moieties, such as pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked), and imidazole moieties such as imidazol-1-yl and imidazol-3-yl (both N-linked), and imidazol-2-yl, imidazol-4-yl and imidazol-5-yl moieties (all of which are C-linked).
  • a“C 3 -C 8 heteroaryl,” is an aromatic C 3 -C 8 heterocycle in which the subscript denotes the total number of carbons of the cyclic ring system of the heterocycle or the total number of aromatic carbons of the aromatic ring system of the heteroaryl and does not implicate the size of the ring system or the presence or absence of ring fusion.
  • C 3 -C 8 heterocycle include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, pyrrolyl, thiophenyl (thiophene), furanyl, thiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, isothiazolyl, and isoxazolyl.
  • the size of the ring system of a heterocycle or heteroaryl is indicated by the total number of atoms in the ring.
  • designation as a 5- or 6- membered heteroaryl indicates the total number of aromatic atoms (i.e., 5 or 6) in the heteroaromatic ring system of the heteroaryl but does not imply the number of aromatic heteroatoms or the number of aromatic carbon atoms in that ring system.
  • Fused heteroaryls are explicitly stated or implied by context as such and are typically indicated by the number of aromatic atoms in each aromatic ring that are fused together to make up the fused heteroaromatic ring system.
  • a 5,6-membered heteroaryl is an aromatic 5- membered ring fused to an aromatic 6-membered ring in which one or both rings have aromatic heteroatom(s) or where a heteroatom is shared between the two rings.
  • a heterocycle fused to an aryl or heteroaryl such that the heterocycle remains non- aromatic and is part of a larger structure through attachment with the non-aromatic portion of the fused ring system is an example of a heterocycle in which the heterocycle is substituted by ring fusion with the aryl or heteroaryl.
  • C 3 -C 8 heterocyclo refers to a C 3 -C 8 heterocyclic defined above wherein one of the hydrogen atoms of the heterocycle is replaced with a bond (i.e., it is divalent).
  • the size of the ring system of a heteroarylene is indicated by the total number of atoms in the ring. For example, designation as a 5- or 6-membered heteroarylene indicates the total number of atoms (i.e., 5 or 6) in the heterocyclic ring system of the heterocycle, but does not imply the number of heteroatoms or the number of carbon atoms in that ring system.
  • a “C 3 -C 8 carbocycle,” by itself or as part of another term, is a 3-, 4-, 5-, 6-, 7- or 8-membered monovalent,saturated or unsaturated non-aromatic monocyclic or bicyclic carbocyclic ring derived by the removal of one hydrogen atom from a ring atom of a parent ring system.
  • Representative -C 3 -C 8 carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5- cycloheptatrienyl, cyclooctyl, and cyclooctadienyl.
  • C 3 -C 8 carbocyclo refers to a C 3 -C 8 carbocycle group defined above wherein another one of the carbocycle group’s hydrogen atoms is replaced with a bond (i.e., it is divalent).
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain hydrocarbon, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to ten, preferably one to three, heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized.
  • the heteroatom(s) O, N and S are placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule.
  • the heteroatom Si is placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.
  • the number of atoms in a heteroalkyl or heteroarylene is indicated by the total number of atoms in the group.
  • designation as a C 1 -C2 heteroalkyl indicates the total number of atoms (i.e., 1 or 2) in the heteroalkyl group, but does not imply the number of heteroatoms or the number of carbon atoms in that group.
  • two heteroatoms are consecutive, such as, for example, -CH 2 -NH- OCH 3 and –CH 2 -O-Si(CH 3 ) 3 .
  • a C1 to C4 heteroalkyl or heteroalkylene has 1 to 4 carbon atoms and 1 or 2 heteroatoms and a C1 to C3 heteroalkyl or heteroalkylene has 1 to 3 carbon atoms and 1 or 2 heteroatoms.
  • a heteroalkyl or heteroalkylene is saturated.
  • heteroalkylene by itself or in combination with another term means a divalent group derived from heteroalkyl (as discussed above), as exemplified by –CH 2 -CH 2 -S-CH 2 -CH 2 - and –CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroalkylene groups heteroatoms can also occupy either or both of the chain termini. Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
  • aminoalkyl by itself or in combination with another term means a heteroalkyl wherein an alkyl moiety as defined herein is substituted with an amino, alkylamino, dialkylamino or cycloalkylamino group.
  • exemplary non-limiting aminoalkyls are —CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 CH 2 NHCH 3 and -CH 2 CH 2 N(CH 3 ) 2 and further includes branched species such as –CH(CH 3 )NH 2 and -C(CH 3 )CH 2 NH 2 in the (R)- or (S)- configuration.
  • an aminoalkyl is an alkyl moiety, group, or substituent as defined herein wherein a sp 3 carbon other than the radical carbon atom of the alkyl moiety has been replaced with an amino or alkylamino moiety wherein its sp 3 nitrogen atom replaces the sp 3 carbon of the alkyl moiety provided that at least one sp 3 carbon atom of the alkyl moiety remains.
  • an aminoalkyl moiety as a substituent to a larger structure or another moiety the aminoalkyl is covalently attached to the structure or moiety through the carbon radical of the alkyl moiety of the aminoalkyl.
  • Hydroalkyl refers to an alkyl moiety, group, or substituent having a hydroxyl radical in place of one or more hydrogen atoms of the alkyl moiety, group, or substituent. In some aspects, one or two hydrogen atoms are each replaced with a hydroxyl substituent in a hydroxyalkyl group.
  • a hydroxyalkyl is typically denoted by the number of contiguous carbon atoms of its alkyl or alkylene moiety.
  • a C 1 hydroxyalkyl is exemplified without limitation by –CH 2 OH
  • a C 2 hydroxyalkyl is exemplified without limitation by –CH 2 CH 2 OH or –CH 2 (OH)CH 3 .
  • a haloalkyl is typically denoted by the number of contiguous carbon atoms of its alkyl or alkylene moiety.
  • a C 1 haloalkyl is exemplified without limitation by –CH 2 F, –CH 2 Cl, –CH 2 Br, or –CH 2 I
  • a C2 haloalkyl is exemplified without limitation by –CH 2 CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 Br, –CH 2 CH 2 I, –CH 2 (F)CH 3 , –CH 2 (Cl)CH 3 , –CH 2 (Br)CH 3 , or —CH 2 (I)CH 3 .
  • haloalkyl refers to an alkyl moiety, group, or substituent having halogens in place of two or more hydrogen atoms.
  • a C1 haloalkyl is also exemplified without limitation by –CHF2, –CHCl2, –CHBr2, or –CHI 2
  • a C 2 haloalkyl is exemplified without limitation by –CH 2 CHF 2 , –CH 2 CHCl 2 , – CH 2 CHBr 2 , –CH 2 CHI 2 , –CH(F) 2 CH 3 , –CH(Cl) 2 CH 3 , –CH(Br) 2 CH 3 , or —CH(I) 2 CH 3 .
  • haloalkyl refers to an alkyl moiety, group, or substituent having halogens in place of all hydrogen atoms.
  • haloalkyl encompasses fully halogenated alkyl moieties, groups, or substituents.
  • a C 1 haloalkyl is also exemplified without limitation by –CF 3 , –CCl 3 , –CBr 3 , or –CI 3 .
  • alkylamino and cycloalkylamino by itself or in combination with another term means an alkyl or cycloalkyl radical, as described herein, wherein the radical carbon atom of the alkyl or cycloalkyl radical has been replaced with a nitrogen radical, provided that at least one sp 3 carbon atom of the alkyl or cycloalkyl radical remains.
  • the resulting substituted radical is sometimes referred to as a dialkylamino moiety, group or substituent wherein the alkyl moieties substituting nitrogen are independently selected.
  • Exemplary and non-limiting amino, alkylamino and dialkylamino substituents include those having the structure of –N(R’) 2 , wherein R’ in these examples are independently hydrogen or C 1-6 alkyl, typically hydrogen or methyl, whereas in cycloalkyl amines, which are included in heterocycloalkyls, both R’ together with the nitrogen to which they are attached define a heterocyclic ring.
  • R’ are hydrogen or alkyl, the moiety is sometimes described as a primary amino group and a tertiary amine group, respectively.
  • one R’ is hydrogen and the other is alkyl, then the moiety is sometimes described as a secondary amino group.
  • Primary and secondary alkylamino moieties are typically more reactive as nucleophiles towards carbonyl-containing electrophilic centers whereas tertiary amines are typically more basic.
  • substituted means that the specified group or moiety bears one or more substituents.
  • alkyl, alkenyl, or alkynyl is substituted with a series of ethyleneoxy moieties to define a PEG Unit as described herein.
  • alkylene, carbocycle, carbocyclo, arylene, heteroalkyl, heteroalkylene, heterocycle, heterocyclo, heteroaryl, and heteroarylene groups as described above are similarly substituted.
  • the term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted is used to described a structural system, the substitution is meant to occur at any valency-allowed position on the system. When a group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another. In some embodiments a substituted group or moiety bears from one to five substituents. In some embodiments a substituted group or moiety bears one substituent.
  • a substituted group or moiety bears two substituents. In some embodiments a substituted group or moiety bears three substituents. In some embodiments a substituted group or moiety bears four substituents. In some embodiments a substituted group or moiety bears five substituents. [0194] By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined herein.
  • protecting groups for atoms or functional groups are given in Greene (1999), “P ROTECTIVE G ROUPS I N O RGANIC S YNTHESIS , 3 RD E D .”, Wiley Interscience, which is incorporated by reference herein.
  • Protecting groups for heteroatoms such as oxygen, sulfur and nitrogen are used in some instances to minimize or avoid unwanted their reactions with electrophilic compounds. In other instances, the protecting group is used to reduce or eliminate the nucleophilicity and/or basicity of the unprotected heteroatom.
  • Non-limiting examples of protected oxygen are given by -OR PR , wherein R PR is a protecting group for hydroxyl, wherein hydroxyl is typically protected as an ester (e.g. acetate, propionate or benzoate).
  • hydroxyl is typically protected as an ether, including alkyl or heterocycloalkyl ethers, (e.g., methyl or tetrahydropyranyl ethers), alkoxymethyl ethers (e.g., methoxymethyl or ethoxymethyl ethers), optionally substituted aryl ethers, and silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), tert- butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS), triisopropylsilyl (TIPS) and [2-(trimethylsilyl)ethoxy]-methylsilyl (SEM)).
  • alkyl or heterocycloalkyl ethers e.g., methyl or tetrahydropyranyl ethers
  • alkoxymethyl ethers e.g., methoxymethyl or e
  • Nitrogen protecting groups include those for primary or secondary amines as in -NHR PR or -N(R PR ) 2 -, wherein least one of R PR is a nitrogen atom protecting group or both R PR together comprise a protecting group.
  • a protecting group is suitable when it is capable of preventing or avoiding unwanted side-reactions or premature loss of the protecting group under reaction conditions required to effect desired chemical transformation elsewhere in the molecule and during purification of the newly formed molecule when desired, and are removable under conditions that do not adversely affect the structure or stereochemical integrity of that newly formed molecule.
  • a suitable protecting group includes those previously described for protecting otherwise reactive functional groups.
  • a suitable protecting group is sometimes a protecting group used in peptide coupling reactions.
  • Electrode withdrawing group as used herein means a functional group or electronegative atom that draws electron density away from an atom to which it is bonded either inductively and/or through resonance, whichever is more dominant (i.e., in some aspects, a functional group or atom is electron withdrawing inductively but is overall electron donating through resonance) and tends to stabilize anions or electron-rich moieties.
  • the electron withdrawing effect is typically transmitted inductively, albeit in attenuated form, to other atoms attached to the bonded atom that has been made electron deficient by the electron withdrawing group (EWG), thus affecting the electrophilicity of a more remote reactive center.
  • Exemplary EWGs can also include aryl groups (e.g., phenyl) depending on substitution of its aromatic ring and certain heteroaryl groups (e.g., pyridine).
  • the term “electron withdrawing groups” also includes aryls or heteroaryls that are further substituted with electron withdrawing groups.
  • an alkyl moiety may also be an electron withdrawing group.
  • “Succinimide moiety” as used herein refers to an organic moiety comprising a succinimide ring system, which is present in one type of Stretcher Unit (Z) that typically further comprises an alkylene-containing moiety bonded to the imide nitrogen of that ring system.
  • a succinimide moiety typically results from Michael addition of a sulfhydryl group of a Ligand Unit to the maleimide ring system of a Stretcher Unit precursor (Z') in a Drug Linker compound or maleimide-containing intermediate thereof.
  • a succinimide moiety therefore comprises a thio-substituted succinimide ring system and when present in a Ligand- Drug Conjugate compound has its imide nitrogen substituted with the remainder of the Linker Unit of the Ligand-Drug Conjugate compound and is optionally substituted with substituent(s) that were present on the maleimide ring system of Z'.
  • succinic acid-amide moiety refers to a succinic acid moiety wherein one of the two carboxylic acid groups is replaced with an amide substituent that results from the thio-substituted succinimide ring system of a succinimide moiety as defined herein having undergone breakage of one of its carbonyl-nitrogen bonds by hydrolysis.
  • the succinic acid-amide moiety has the structure:
  • Hydrolysis of the succinimide ring system of the thio-substituted succinimide moiety is expected to provide regiochemical isomers of acid-amide moieties that are due to differences in reactivity of the two carbonyl carbons of the succinimide ring system attributable at least in part to any substituent present in the maleimide ring system of the Stretcher Unit precursor and to the thio substituent introduced by the targeting ligand, which is a precursor to the Ligand Unit.
  • the assembly of the conjugates, linkers and components described herein will refer to reactive groups.
  • a “reactive group” or RG is a group that contains a reactive site (RS) capable of forming a bond with either the components of the Linker Unit Q or the Drug Unit D.
  • RS is the reactive site within a Reactive Group (RG).
  • Reactive groups include sulfhydryl groups to form disulfide bonds or thioether bonds, aldehyde, ketone, or hydrazine groups to form hydrazone bonds, carboxylic or amino groups to form peptide bonds, carboxylic or hydroxy groups to form ester bonds, sulfonic acids to form sulfonamide bonds, alcohols to form carbamate bonds, and amines to form sulfonamide bonds or carbamate bonds.
  • the following table is illustrative of Reactive Groups, Reactive Sites, and exemplary functional groups capable of forming after reaction of the reactive site.
  • the table is not limiting.
  • One of skill in the art will appreciate that the noted R * and R ** portions in the table are effectively any organic moiety (e.g., an alkyl group, aryl group, heteroaryl group, or substituted alkyl, aryl, or heteroaryl, group) that is compatible with the bond formation provided in converting RG to one of the Exemplary Functional Groups.
  • R * represents one or more components of the self-stabilizing linker or optional secondary linker
  • R ** represents one or more components of the optional secondary linker, Drug Unit, stabilizing unit, or detection unit.
  • the hydrophobicity of auristatin drugs is a known barrier to their implementation in pharmaceuticals, including Ligand-Drug Conjugates, due to the potential for off-target toxicity due to high bystander activity and rapid clearance of the drug from the body of subjects.
  • the compounds of the present application attenuate the hydphobicity of the Drug Unit, which in turn attentuates the off-target toxicity and rapid clearance of the drugs.
  • the use of Drug Units with polar moieities in certain locations on the auristatin backbone leads to decreased permeability and on-cell potency of the free drug, and thus fewer off-target effects during treatment, without sacrificing efficacy of intact Ligand-Drug Conjugate compounds that incorporate the Drug Units.
  • auristatin compounds comprising at least one polar moiety on the auristatin backbone.
  • Drug-Linker compounds comprising an auristatin moiety, as described herein.
  • Ligand-Drug Conjugate compounds comprising an auristatin moiety, as described herein.
  • methods of treating cancer using the Ligand-Drug Conjugate compounds described herein are methods of making auristatin compounds comprising at least one hydrophilic moiety, Drug-Linkers thereof and their intermediates, and Ligand-Drug Conjugate compounds thereof.
  • the polar moiety is a polar moiety other than carboxylate. In some embodiments, the polar moiety is a hydroxyl group.
  • compound of Formula (II) or a salt thereof, wherein R 1 , R 3 , and R 4 are independently H or C 1 -C 4 alkyl; R 6 is C 1 -C 4 alkyl optionally substituted with OH; R 7 is H, C 1 -C 4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH; n is 0, 1, or 2; and q is 0 or 1. [0208] In some embodiments of Formula (I), q is 0. In some embodiments of Formula (I), q is 1.
  • q is 0. In some embodiments of Formula (II), q is 1.
  • X b is -NR 1 R 2 is and X a is .
  • R 1 and R 2 are each independently C 1 -C 4 alkyl. In some embodiments, R 1 and R 2 are both H. In some embodiments, R 1 and R 2 are each independently n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 1 and R 2 are each independently ethyl or methyl. In some embodiments, R 1 and R 2 are both methyl.
  • R 1 is H and R 2 is C 1 -C 4 alkyl. In some embodiments, R 1 is H and R 2 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 1 is H and R 2 is ethyl or methyl. In some embodiments, R 1 is H and R 2 is methyl. In some emodiments, R 3 and R 4 are each independently C 1 -C 4 alkyl. In some embodiments, R 3 is H and R 4 is C 1 -C 4 alkyl. In some embodiments, R 3 and R 4 are H. In some embodiments, R 3 is H and R 4 is methyl. In some embodiments, n is 0, 1, 2, or 3.
  • n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, R 1 is H, R 2 is methyl, R 3 is H, R 4 is H, and n is 0. In some embodiments, R 1 is methyl, R 2 is methyl, R 3 is H, R 4 is H, and n is 0. [0210] In some embodiments of Formula (I) or (Iz), X a and X b are taken together with the carbon atom to which they are attached to form , wherein the asterisk denotes the carbon atom of Formula (I) that bears the X a and X b groups.
  • R 5 is H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 5 is H, ethyl, or methyl. In some embodiments, R 5 is H or methyl. In some embodiments, R 5 is ethyl or methyl. In some embodiments, R 5 is H. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is methyl. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 2. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.
  • n is 0 or 1 and m is 0, 1, or 2. In some embodiments, n is 0 and m is 2. In some embodiments, n is 1 and m is 1. In some embodiments, m is 2 and n is 1. In some embodiments, X is H or OH. In some embodiments, X is H. In some embodiments, X is OH.
  • X is H, OH, -C(O)NR a R b , -S(O) 2 R a , -S(O)-R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a .
  • X is OH, -S(O) 2 R a , -S(O)-R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a .
  • X is H or OH.
  • X is OH. In some embodiments, X is OH, -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is OH, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b . In some embodiments, X is -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is H, OH, -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is H, OH, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b . In some embodiments, X is H, -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is H, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is H, OH, or -C(O)NR a R b . In some embodiments, X is OH or -C(O)NR a R b . In some embodiments, X is H or -C(O)NR a R b . In some embodiments, R a and R b are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a and R b are independently H, ethyl, or methyl. In some embodiments, R a and R b are independently H or methyl.
  • R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a is H and R b is methyl.
  • X is OH, -C(O)NR a R b , -S(O) 2 R a , -S(O)-R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a .
  • X is OH.
  • X is OH, -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is OH, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b . In some embodiments, X is -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is OH or -C(O)NR a R b . In some embodiments, X is -C(O)NR a R b . In some embodiments, R a and R b are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a and R b are independently H, ethyl, or methyl. In some embodiments, R a and R b are independently H or methyl. In some embodiments, R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a is H and R b is methyl.
  • X b is -NR 1 R 2 is and X a is X is OH, R 1 is H or methyl, R 2 is methyl, R 3 is H, R 4 is H, and n is 0.
  • X is OH, R 1 is methyl, R 2 is methyl, R 3 is H, R 4 is H, and n is 0.
  • X is OH, R 1 is H, R 2 is methyl, R 3 is H, R 4 is H, and n is 0.
  • X is OH, R 1 is H, R 2 is methyl, R 3 is H, R 4 is H, and n is 0.
  • X is OH, R 3 and R 4 are H, and n is 0.
  • X is OH, R 1 is H, R 2 is H, R 3 is H, R 4 is H, and n is 0. [0214]
  • R 1 is H, n-propyl, isopropyl, ethyl, or methyl.
  • R 1 is H, ethyl, or methyl.
  • R 1 is H or methyl.
  • R 1 is ethyl.
  • R 1 is methyl.
  • R 1 is H.
  • n is 0 or 1.
  • n is 1. In some embodiments, n is 0.
  • R 3 and R 4 are H. In some embodiments, R 3 and R 4 are methyl. In some embodiments, R 3 is H and R 4 is methyl. [0216] In some embodiments or Formula (I), (Iz), or (II), R 6 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R 6 is isopropyl substituted with OH.
  • R 6 is ethyl substituted with OH. In some embodiments, R 6 is methyl substituted with OH.
  • R 7 is C 1 -C 4 alkyl substituted with OH. In some embodiments, R 7 is C 1 -C 4 alkyl subsituted by two OH moieties. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R 7 is C 1 -C 4 alkyl.
  • R 7 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is -CH 2 CH 2 OH or CH 2 OH. In some embodiments, R 7 is -CH 2 OH. In some embodiments, R 7 is 5-6 membered heteroaryl. In some embodiments, R 7 is 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl. [0218] In some embodiments of Formula (I), (Iz), or (II), R 8 , R 9 , and R 11 are H. In some embodiments, R 8 is OH, R 9 is H, and R 11 is H.
  • R 8 and R 9 are each OH and R 11 is H. In some embodiments, R 8 is OH, R 9 is H, and R 11 is OH. In some embodiments, R 8 is H, R 9 is H, and R 11 is OH.
  • E is a 6-membered ring. In some embodiments, E is pyridine or phenyl. In some embodiments, E is phenyl. [0220] In some embodiments of Formula (I), (Iz), or (II), R 7 is -CH 2 OH, R 8 is H, R 9 is H, and E is phenyl.
  • a compound of Formula (Ia): or a salt thereof wherein R 1 , R 2 , R 3 , R 4 , R a , and R b are each independently H or C 1 -C 4 alkyl;
  • X is H, OH, -C(O)NR a R b , -S(O) 2 R a , -S(O)-R a -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a ;
  • R 6 is C 1 -C 4 alkyl;
  • R 7 is H, C 1 -C 4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl;
  • R 8 , R 9 , and R 11 are each independently H or OH; q is 0 or 1; and wherein when X is H, at least two of R 7 , R 8 , R
  • R 1 is H and R 2 is C 1 -C 4 -alkyl. In some embodiments, R 1 is H and R 2 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 1 is H and R 2 is ethyl or methyl. In some embodiments, R 1 is H and R 2 is methyl. In some embodiments, R 1 and R 2 are each independently C 1 -C 4 alkyl.
  • R 1 and R 2 are each independently n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 1 and R 2 are each independently ethyl or methyl. In some embodiments, R 1 and R 2 are methyl. In some embodiments, R 1 and R 2 are both H. [0224] In some embodiments of Formula (Ia), X is H, OH, -C(O)NR a R b , -S(O) 2 R a , -S(O)- R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a .
  • X is OH, -S(O) 2 R a , -S(O)-R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a .
  • X is H or OH.
  • X is OH.
  • X is OH, -NHS(O) 2 R a , or -NHC(O)R a .
  • X is OH, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b . In some embodiments, X is H, OH, -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is H, OH, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is H, -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is H, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b . In some embodiments, X is H, OH, or -C(O)NR a R b . In some embodiments, X is OH or -C(O)NR a R b . In some embodiments, X is H or -C(O)NR a R b .
  • R a and R b are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a and R b are independently H, ethyl, or methyl. In some embodiments, R a and R b are independently H or methyl. In some embodiments, R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a is H and R b is methyl.
  • X is OH, -C(O)NR a R b , -S(O) 2 R a , -S(O)-R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a .
  • X is OH.
  • X is OH, -NHS(O) 2 R a , or -NHC(O)R a .
  • X is OH, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is -NHS(O) 2 R a , or -NHC(O)R a .
  • X is -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is OH or -C(O)NR a R b .
  • X is -C(O)NR a R b .
  • R a and R b are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a and R b are independently H, ethyl, or methyl. In some embodiments, R a and R b are independently H or methyl. In some embodiments, R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a is H and R b is methyl. [0226] In some embodiments of Formula (Ia), R 6 is n-propyl, isopropyl, ethyl, or methyl.
  • R 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6 is methyl substituted with OH. [0227] In some embodiments of Formula (Ia), R 7 is C 1 -C 4 alkyl substituted with OH.
  • R 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R 7 is -CH 2 CH 2 OH or CH 2 OH. In some embodiments, R 7 is -CH 2 OH. In some embodiments, R 7 is C 1 -C 4 alkyl. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is 5-6 membered heteroaryl. In some embodiments, R 7 is 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl.
  • R 8 , R 9 , and R 11 are H.
  • R 8 is OH, R 9 is H, and R 11 is H.
  • R 8 and R 9 are each OH and R 11 is H.
  • R 8 is OH, R 9 is H, and R 11 is OH.
  • X is OH, R 3 is H or methyl, R 1 is H or C 1 - C4 alkyl, R 2 is C 1 -C 4 alkyl, R6 is C 1 -C 4 alkyl, R 7 is C 1 -C 4 alkyl optionally substituted with OH, R 8 is H or C 1 -C 4 alkyl, R 9 is H, and q is 0.
  • X is OH, R 3 is H, R 1 is H or methyl, R 2 is methyl, R 6 is isopropyl, R 7 is CH 2 OH, R 8 is H, R 9 is H, and q is 0.
  • X is H. In some embodiments, X is H or OH. In some embodiments, R 5 is H or methyl. In some embodiments, R 5 is H. In some embodiments, m is 1 or 2. In some embodiments, m is 2. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, m is 2 and n is 0. In some embodiments, m is 1 and n is 1.
  • R 6 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6 is methyl substituted with OH.
  • R 7 is C 1 -C 4 alkyl substituted with OH.
  • R 7 is n-propyl, isopropyl, ethyl, or methyl, each of which substituted with OH.
  • R 7 is C 1 -C 4 alkyl.
  • R 7 is n-propyl, isopropyl, ethyl, or methyl.
  • R 7 is methyl.
  • R 7 is -CH 2 CH 2 OH or CH 2 OH.
  • R 7 is -CH 2 OH.
  • R 7 is 5-6 membered heteroaryl.
  • R 7 is 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl.
  • R 8 , R 9 , and R 11 are each H. In some embodiments, R 8 is OH, R 9 is H, and R 11 is H. In some embodiments, R 8 and R 9 are each OH and R 11 is H. In some embodiments, R 8 is OH, R 9 is H, and R 11 is OH. In some embodiments, R 8 is H, R 9 is H, and R 11 is OH.
  • E is a 6-membered ring. In some embodiments, E is pyridine or phenyl.
  • E is phenyl.
  • R 7 is -CH 2 OH, R 8 is H, R 9 is H, and E is phenyl.
  • R 7 is -CH 2 OH, R 8 is H, and R 9 is H.
  • m is 2, n is 0, X is H, R 10 is methyl, R 6 is isopropyl, R 7 is H, R 8 is OH, and R 9 is OH.
  • m is 1, n is 1, X is H, R 10 is methyl, R 6 is isopropyl, R 7 is H, R 8 is OH, and R 9 is OH.
  • m is 2, n is 1, X is H, R 10 is methyl, R 6 is isopropyl, R 7 is H, R 8 is OH, and R 9 is OH.
  • R 1 and R 1 are both H.
  • R 1 is H and R 2 is C 1 -C 4 -alkyl.
  • R 1 is H and R 2 is n-propyl, isopropyl, ethyl, or methyl.
  • R 1 is H and R 2 is ethyl or methyl. In some embodiments, R 1 is H and R 2 is methyl. In some embodiments, R 1 and R 2 are each independently C 1 -C 4 alkyl. In some embodiments, R 1 and R 2 are each independently n- propyl, isopropyl, ethyl, or methyl. In some embodiments, R 1 and R 2 are each independently ethyl or methyl. In some embodiments, R 1 and R 2 are methyl.
  • X is H, OH, -C(O)NR a R b , or -NHC(O)R a .
  • X is H, OH, -C(O)NR a R b , or -NHC(O)R a .
  • X is H or OH.
  • X is OH.
  • R 3 is H or C 1 -C 4 alkyl.
  • R 3 is H, n-propyl, isopropyl, ethyl, or methyl.
  • R 3 is H, ethyl, or methyl.
  • X is H or OH and R 3 is H or methyl.
  • X is OH and R 3 is H.
  • X is OH and R 3 is methyl.
  • R a is ethyl or methyl.
  • R a is methyl.
  • R 6 is n-propyl, isopropyl, ethyl, or methyl.
  • R 6 is ethyl or methyl.
  • R 6 is is isopropyl.
  • R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6 is methyl substituted with OH. [0245] In some embodiments of Formula (Ic), (Id), (Ie), or (If), R 7 is C 1 -C 4 alkyl substituted with OH. In some embodiments, R 7 is C 1 -C 4 alkyl subsituted by two OH moieties.
  • R 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R 7 is -CH 2 CH 2 OH or CH 2 OH. In some embodiments, R 7 is -CH 2 OH. In some embodiments, R 7 is C 1 -C 4 alkyl. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is 5-6 membered heteroaryl. In some embodiments, R 7 is 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl.
  • R 8 and R 9 are H. In some embodiments, R 8 is OH and R 9 is H. In some embodiments, R 8 and R 9 are each OH. [0247] In some embodiments of Formaul (Id) or (If), R 8 , R 9 , and R 11 are H. In some embodiments, R 8 is OH, R 9 is H, and R 11 is H. In some embodiments, R 8 and R 9 are each OH and R 11 is H. In some embodiments, R 8 is OH, R 9 is H, and R 11 is OH. In some embodiments, R 8 is H, R 9 is H, and R 11 is OH. In some embodiments, R 8 is H, R 9 is H, and R 11 is OH.
  • X is OH, R 3 is H or methyl, R 1 is H or C 1 -C 4 alkyl, R 2 is C 1 -C 4 alkyl, R 6 is C 1 -C 4 alkyl, R 7 is C 1 -C 4 alkyl optionally substituted with OH, R 8 is H or C 1 -C 4 alkyl, and R 9 is H.
  • X is OH, R 3 is H, R 1 is H or methyl, R 2 is methyl, R 6 is is isopropyl, R 7 is CH 2 OH, R 8 is H, and R 9 is H.
  • R 7 is -CH 2 OH
  • R 8 is H
  • R 9 is H.
  • provided is a compound of Formula (IIa): or a salt thereof, wherein the variables are as defined for Formula (II).
  • q is 0.
  • q is 1.
  • R 1 is H, n-propyl, isopropyl, ethyl, or methyl.
  • R 1 is H, ethyl, or methyl.
  • R 1 is H or methyl.
  • R 1 is ethyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is H. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0. [0253] In some embodiments or Formula (IIa), R 6 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH.
  • R 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6 is methyl substituted with OH.
  • R 7 is C 1 -C 4 alkyl substituted with OH. In some embodiments, R 7 is C 1 -C 4 alkyl subsituted by two OH moieties. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R 7 is C 1 -C 4 alkyl.
  • R 7 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is -CH 2 CH 2 OH or CH 2 OH. In some embodiments, R 7 is -CH 2 OH. In some embodiments, R 7 is 5-6 membered heteroaryl. In some embodiments, R 7 is 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl. [0255] In some embodiments of Formula (IIa), R 8 , R 9 , and R 11 are H. In some embodiments, R 8 is OH, R 9 is H, and R 11 is H.
  • R 8 and R 9 are each OH and R 11 is H. In some embodiments, R 8 is OH, R 9 is H, and R 11 is OH. In some embodiments, R 8 is H, R 9 is H, and R 11 is OH.
  • E is a 6-membered ring. In some embodiments, E is pyridine or phenyl. In some embodiments, E is phenyl.
  • R 7 is -CH 2 OH
  • R 8 is H
  • R 9 is H
  • R 11 is H.
  • provided is a compound of Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt). Table 1. Hydrophilic auristatin compounds
  • Drug-Linker Compounds [0259]
  • Drug-Linker compounds when preparing Ligand-Drug Conjugate compounds described herein, it will be desirable to synthesize the full Drug-Linker compound prior to conjugation to a targeting agent, which becomes the Ligand Unit of the Ligand-Drug conjugate compound.
  • Drug-Linker compounds as described herein are intermediate compounds.
  • the Stretcher Unit in a Drug-Linker compound is not yet covalently attached to the Ligand Unit (i.e., is a Stretcher Unit precursor, Z'), and therefore has a functional group for conjugation to a targeting agent.
  • a Drug-Linker compound comprises an auristatin moiety (shown herein as Formulae (I) and (II), or any subformula thereof) or, and a Linker Unit (Q) through which the Ligand Unit is connected to the Drug Unit.
  • a Drug-Linker compound comprises an auristatin compound of Formula (I), or any subformula thereof, as a Drug Unit and a Linker Unit (Q) comprising a Releasable Linker (RL) that is other than a Glycoside (e.g., Glucuronide) Unit through which the Ligand Unit is connected to the conjugated auristatin compound.
  • RL Releasable Linker
  • the Linker Unit comprises, in addition to RL, a Stretcher Unit precursor (Z') comprising a functional group for conjugation to a targeting agent that is the precursor to the Ligand Unit and thus is capable of (directly or indirectly) connecting the RL to the Ligand Unit.
  • a Parallel Connector Unit (B) is present when it is desired to add a Partitioning Agent (S * ) as a side chain appendage.
  • a Connector Unit (A) is present when it is desirable to add more distance between the Stretcher Unit and RL.
  • a Drug-Linker compound comprises an auristatin compound of Formula (I), or any subformula thereof, and a Linker Unit (Q), wherein Q comprises a Releasable Linker (RL) that is a Glycoside (e.g., Glucuronide) Unit, directly attached to a Stretcher Unit precursor (Z') or indirectly to Z' through attachment to intervening component(s) of the Drug-Linker compound’s Linker Unit (i.e., A, S * and/or B(S * )), wherein Z' comprises a functional group capable of forming a covalent bond to a targeting agent.
  • RL Releasable Linker
  • a Drug-Linker compound comprises an auristatin of Formula (I), or any subformula thereof, and a Linker Unit (Q), wherein Q comprises a Releasable Linker (RL) that is other than a Glycoside (e.g., Glucuronide) Unit (RL), directly attached to a Stretcher Unit precursor (Z') or indirectly to Z' through attachment to intervening component(s) of the Drug-Linker compound’s Linker Unit (i.e., A, S * and/or B(S * )), wherein Z' comprises a functional group capable of forming a covalent bond to a targeting agent.
  • Q comprises a Releasable Linker (RL) that is other than a Glycoside (e.g., Glucuronide) Unit (RL), directly attached to a Stretcher Unit precursor (Z') or indirectly to Z' through attachment to intervening component(s) of the Drug-Linker compound’s Linker Unit (i.e., A, S * and/
  • the Drug-Linker compound has the formula: Q-D, or a salt thereof, wherein Q is a Linker Unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S * -RL-, (iv) Z'-A-S * -RL-Y-, (v) Z'-A-B(S * )-RL-, (vi) Z'-A-B(S * )-RL-Y-, (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-; Z' is a Stretcher Unit precursor; A is a bond or a Connector Unit; B is a Parallel Connector Unit; S *
  • Drug Unit D [0265] The Drug Units of the Drug-Linker compounds, or Ligand-Drug Conjugate thereof, provided herein are auristatin moieities of the compounds disclosed herein and are referred to herein as Drug Units. [0266] In some embodiments, the Drug Unit D has Formula (I'), as described above. [0267] In some embodiments of Formula (I'), q is 0.
  • the Drug Unit D has Formula (Iz'): wherein X b is -NR 2 - # or -N + R 1 R 5 - # , wherein the # denotes the point of attachment to Q, and X a ken together with the carbon atom to which they are attached to form wherein the asterisk denotes the carbon atom of Formula (I) that bears the X a and X b groups, and the # denotes the point of attachment to Q; R 1 and R 5 are independently C 1 -C 4 alkyl; X is OH, -C(O)NR a R b , -S(O) 2 R a , -S(O)-R a -S(O) 2 NR a R b , -NHS(O) 2 R a , or - NHC(O)R a ; R 2 , R 3 , R 4 , R 10 ,
  • q is 0. In some embodiments, q is 1.
  • X b is -NR 2 - # or -N + R 1 R 5 - # , wherein the # denotes the point of attachment to Q, and X a is .
  • R 1 and R 2 are each independently C 1 -C 4 alkyl.
  • R 1 and R 5 are each independently n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 1 and R 5 are each independently ethyl or methyl.
  • R 1 and R 5 are methyl.
  • R 3 and R 4 are each independently C 1 -C 4 alkyl.
  • R 3 is H and R 4 is C 1 -C 4 alkyl.
  • R 3 and R 4 are H.
  • R 3 is H and R 4 is methyl.
  • n is 0, 1, 2, or 3.
  • n is 0, 1, or 2.
  • n is 0 or 1.
  • n is 1.
  • n is 0.
  • R 1 is methyl
  • R 5 is methyl
  • R 3 is H
  • R 4 is H
  • n is 0.
  • R 2 is n-propyl, isopropyl, ethyl or methyl. In some embodiments, R 2 is ethyl or methyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is H. [0271] In some embodiments of Formula (I') or (Iz'), X a and X b are taken together with the carbon atom to which they are attached to form , wherein the asterisk denotes the carbon atom of Formula (I) that bears the X a and X b groups, and the # denotes the point of attachment to Q. In some embodiments, R 5 is n-propyl, isopropyl, ethyl, or methyl.
  • R 5 is ethyl or methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is methyl. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 2. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, m is 1 or 2 and n is 0 or 1.
  • X is H, OH, -C(O)NR a R b , -S(O) 2 R a , -S(O)-R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a .
  • X is OH, -S(O) 2 R a , -S(O)-R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a .
  • X is H or OH.
  • X is OH. In some embodiments, X is OH, -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is OH, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b . In some embodiments, X is -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is H, OH, -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is H, OH, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b . In some embodiments, X is H, -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is H, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is H, OH, or -C(O)NR a R b . In some embodiments, X is OH or -C(O)NR a R b . In some embodiments, X is H or -C(O)NR a R b . In some embodiments, R a and R b are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a and R b are independently H, ethyl, or methyl. In some embodiments, R a and R b are independently H or methyl.
  • R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a is H and R b is methyl.
  • X is OH, -C(O)NR a R b , -S(O) 2 R a , -S(O)- R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a .
  • X is OH.
  • X is OH, -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is OH, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b . In some embodiments, X is -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is OH or -C(O)NR a R b . In some embodiments, X is -C(O)NR a R b . In some embodiments, R a and R b are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a and R b are independently H, ethyl, or methyl. In some embodiments, R a and R b are independently H or methyl. In some embodiments, R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a is H and R b is methyl.
  • X b is-N + R 1 R 5 - # and X a is X is OH, R 1 is methyl or methyl, R 5 is methyl, R 3 is H, R 4 is H, and n is 0.
  • X is OH, R 1 is methyl, R 5 is methyl, R 3 is H, R 4 is H, and n is 0.
  • X is OH, R 3 and R 4 are H, and n is 0.
  • X b is -NR 2 - # , X a is , X is OH, and R 2 is H or C 1 -C 4 alkyl.
  • X b is -NR 2 - # and X a is X is OH, and R 2 is H.
  • X b is -NR 2 - # and X a is X is OH, and R 2 is C 1 -C 4 alkyl.
  • R 6 is n-propyl, isopropyl, ethyl, or methyl.
  • R 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6 is methyl substituted with OH. [0277] In some embodiments of Formula (I') or (Iz'), R 7 is C 1 -C 4 alkyl substituted with OH. In some embodiments, R 7 is C 1 -C 4 alkyl substituted by two OH moieties.
  • R 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R 7 is C 1 -C 4 alkyl. In some embodiments, R 7 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 7 is methyl. In some embodiments, R 7 is -CH 2 CH 2 OH or CH 2 OH. In some embodiments, R 7 is -CH 2 OH. In some embodiments, R 7 is 5-6 membered heteroaryl. In some embodiments, R 7 is 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl.
  • R 8 , R 9 , and R 11 are H.
  • R 8 is OH, R 9 is H, and R 11 is H.
  • R 8 and R 9 are each OH and R 11 is H.
  • R 8 is OH, R 9 is H, and R 11 is OH.
  • R 8 is H, R 9 is H, and R 11 is OH.
  • E is an optionally substituted 6- membered ring.
  • E is pyridine or phenyl, each of which is optionally substituted.
  • E is optionally substituted phenyl. In some embodiments, E is optionally substituted 5-6 membered heteroaryl. In some embodiments, E is optionally substituted 5-membered heteroaryl. In some embodiments, E is pyridine or phenyl, each of which is unsubstituted. In some embodiments, E is unsubstituted phenyl. In some embodiments, E is unsubstituted 5-6 membered heteroaryl. In some embodiments, E is unsubstituted 5-membered heteroaryl. [0280] In some embodiments of Formula (I') or (Iz'), R 7 is -CH 2 OH, R 8 is H, R 9 is H, and E is phenyl.
  • the Drug Unit D has Formula (Ia') or (Ia''): or a salt thereof, wherein R 1 and R 5 are independently C 1 -C 4 alkyl; X is H, OH, -C(O)NR a R b , -S(O) 2 R a , -S(O)-R a -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a ; R 2 , R 3 , R a , and R b are each independently H or C 1 -C 4 alkyl; R 6 is C 1 -C 4 alkyl; R 7 is H, C 1 -C 4 alkyl optionally substituted with OH, or 5-6 membered heteroaryl; R 8 , R 9 , and R 11 are each independently H or OH; q is 0 or 1; and the wavy line is the site of attachment to
  • R 2 is C 1 -C 4 -alkyl. In some embodiments, R 2 is n-propyl, isopropyl, ethyl, or methyl. R 2 is ethyl or methyl. R 2 is methyl. In some embodiments, R 2 is H. In some embodiments, R 2 is ethyl, methyl, or H. In some embodiments, R 2 is methyl or H.
  • R 1 and R 5 are each independently n- propyl, isopropyl, ethyl, or methyl. In some embodiments, R 1 and R 5 are each independently ethyl or methyl. In some embodiments, R 1 and R 5 are each methyl. In some embodiments, R 1 is methyl and R 5 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 1 is methyl and R 5 is ethyl or methyl. In some embodiments, R 1 and R 5 are methyl.
  • X is H, OH, -C(O)NR a R b , -S(O) 2 R a , -S(O)-R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a .
  • X is OH, -S(O) 2 R a , -S(O)-R a , -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a .
  • X is H or OH. In some embodiments, X is OH. In some embodiments, X is OH, -NHS(O) 2 R a , or -NHC(O)R a . In some embodiments, X is OH, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b . In some embodiments, X is -NHS(O) 2 R a , or -NHC(O)R a .
  • X is -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is H, OH, -NHS(O) 2 R a , or -NHC(O)R a .
  • X is H, OH, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is H, -NHS(O) 2 R a , or -NHC(O)R a .
  • X is H, -S(O) 2 R a , -S(O)-R a , or -S(O) 2 NR a R b .
  • X is H, OH, or -C(O)NR a R b .
  • X is OH or -C(O)NR a R b .
  • X is H or -C(O)NR a R b .
  • R a and R b are independently H, n-propyl, isopropyl, ethyl, or methyl.
  • R a and R b are independently H, ethyl, or methyl. In some embodiments, R a and R b are independently H or methyl. In some embodiments, R a is H and R b is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R a is H and R b is methyl. [0286] In some embodiments of Formula (Ia') and (Ia''), R 3 is H or methyl. In some embodiments, R 3 is H. In some embodiments, R 3 is methyl.
  • R 6 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R 6 is ethyl or methyl. In some embodiments, R 6 is isopropyl. In some embodiments, R 6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R 6 is isopropyl substituted with OH. In some embodiments, R 6 is ethyl substituted with OH. In some embodiments, R 6 is methyl substituted with OH.
  • R 7 is C 1 -C 4 alkyl substituted with OH.
  • R 7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH.
  • R 7 is -CH 2 CH 2 OH or CH 2 OH.
  • R 7 is -CH 2 OH.
  • R 7 is C 1 -C 4 alkyl.
  • R 7 is n-propyl, isopropyl, ethyl, or methyl.
  • R 7 is methyl.
  • R 7 is 5-6 membered heteroaryl. In some embodiments, R 7 is 5-membered heteroaryl. In some embodiments, R 7 is thiazolyl. [0289] In some embodiments of Formula (Ia') and (Ia''), R 8 , R 9 , and R 11 are H. In some embodiments, R 8 is OH, R 9 is H, and R 11 is H. In some embodiments, R 8 and R 9 are each OH and R 11 is H. In some embodiments, R 8 is OH, R 9 is H, and R 11 is OH. In some embodiments, R 8 is H, R 9 is H, and R 11 is OH. In some embodiments, R 8 is H, R 9 is H, and R 11 is OH.
  • X is OH, R 3 is H or methyl, R 2 is C 1 -C 4 alkyl, R 6 is C 1 -C 4 alkyl, R 7 is C 1 -C 4 alkyl optionally substituted with OH, R 8 is H or C 1 -C 4 alkyl, and R 9 is H.
  • q is 0, X is OH, R 3 is H or methyl, R 2 is C 1 -C 4 alkyl, R6 is C 1 -C 4 alkyl, R 7 is C 1 -C 4 alkyl optionally substituted with OH, R 8 is H or C 1 -C 4 alkyl, and R 9 is H.
  • X is OH
  • R 3 is H or methyl
  • R 5 is C 1 -C 4 alkyl
  • R6 is C 1 -C 4 alkyl
  • R 7 is C 1 -C 4 alkyl optionally substituted with OH
  • R 8 is H or C 1 -C 4 alkyl
  • R 9 is H.
  • q is 0, X is OH, R 3 is H or methyl, R 1 C 1 -C 4 alkyl, R 5 is C 1 -C 4 alkyl, R 6 is C 1 -C 4 alkyl, R 7 is C 1 -C 4 alkyl optionally substituted with OH, R 8 is H or C 1 -C 4 alkyl, and R 9 is H.
  • of the Drug Unit D has Formula (Ib') or (Ib''): wherein the variables are as defined for Formula (Ib) and the wavy line is the site of attachment to the rest of the Drug-Linker compound.
  • R 7 is -CH 2 OH, R 8 is H, and R 9 is .
  • the Drug Unit D has Formula (Ic') or (Ic''): wherein the variables are as defined for Formula (Ic) and the wavy line is the site of attachment to the rest of the Drug-Linker compound.
  • X is OH and R 3 is H.
  • R 7 is -CH 2 OH, R 8 is H, and R 9 is H.
  • X is OH, R 7 is -CH 2 OH, R 8 is H, and R 9 is H.
  • X is OH, R 3 is H, R 7 is -CH 2 OH, R 8 is H, and R 9 is H.
  • the Drug Unit D has the Formula (Id') or (Id''):
  • the Drug Unit D has Formula (Ie') or (Ie''): wherein the variables are as defined for Formula (Ie) and the wavy line is the site of attachment to the rest of the Drug-Linker compound. [0298] In some embodiments, the Drug Unit D has the Formula (Id') or (Id''): wherein the variables are as defined for Formula (If) and the wavy line is the site of attachement to the rest of the Drug-Linker compound.
  • X is OH and R 3 is H.
  • R 7 is -CH 2 OH, R 8 is H, and R 9 is H.
  • X is OH, R 7 is -CH 2 OH, R 8 is H, and R 9 is H.
  • X is OH, R 3 is H, R 7 is -CH 2 OH, R 8 is H, and R 9 is H.
  • the quaternized nitrogen atom prevents cyclization of the Drug Unit. In some embodiments, the quaternized nitrogen atom prevents premature release of the Drug Unit from the Drug-Linker compound or moiety (e.g., in a Ligand-Drug Conjugate compound). In some embodiments, the quaternized nitrogen atom prevents cyclization and premature release of the Drug Unit from the Drug-Linker compound or moiety (e.g., in a Ligand-Drug Conjugate compound). 2.
  • the Linker Unit Q has a formula selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S * -RL-, (iv) Z'-A-S * -RL-Y-, (v) Z'-A-B(S * )-RL-, (vi) Z'-A-B(S * )-RL-Y-, (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-; wherein Z' is a Stretcher Unit; A is a bond or a Connector Unit; B is a Parallel Connector Unit; S * is a Partitioning Agent; RL is
  • the Linker Unit Q has a formula selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S * -RL-, (iv) Z'-A-S * -RL-Y-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-.
  • the Linker Unit Q has a formula selected from the group consisting of: (v) Z'-A-B(S * )-RL-, (vi) Z'-A-B(S * )-RL-Y-, (ix) Z'-A-B(S*)-W-, and (xi) Z'-A-B(S*)-W-RL-.
  • the Linker Unit Q has a formula selected from the group consisting of: (iii) Z'-A-S * -RL-, (iv) Z'-A-S * -RL-Y-, (v) Z'-A-B(S * )-RL-, (vi) Z'-A-B(S * )-RL-Y-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-.
  • the Linker Unit Q has a formula selected from the group consisting of: (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-. 3.
  • Stretcher Unit Z' [0306] A Stretcher Unit (Z) is a component of a Ligand-Drug Conjugate that acts to connect the Ligand Unit to the remainder of the conjugate.
  • a Stretcher Unit precursor (Z') is a component of a Drug-Linker compound or intermediate thereof has a functional group that can form a bond with a functional group of a targeting ligand to form a Stretcher Unit (Z).
  • a Stretcher Unit precursor (Z') has an electrophilic group that is capable of interacting with a reactive nucleophilic group present on a Ligand Unit (e.g., an antibody) to provide a covalent bond between a Ligand Unit and the Stretcher Unit of a Linker Unit.
  • Nucleophilic groups on an antibody having that capability include but are not limited to, sulfhydryl, hydroxyl and amino functional groups.
  • the heteroatom of the nucleophilic group of an antibody is reactive to an electrophilic group on a Stretcher Unit precursor and can provide a covalent bond between the Ligand Unit and Stretcher Unit of a Linker Unit or Drug-Linker moiety.
  • Useful electrophilic groups for that purpose include, but are not limited to, maleimide, haloacetamide groups, and NHS esters.
  • the electrophilic group provides a convenient site for antibody attachment to form a Ligand- Drug Conjugate compound or Ligand Unit-Linker intermediate compound.
  • a Stretcher Unit precursor has a reactive site which has a nucleophilic group that is reactive to an electrophilic group present on a Ligand Unit (e.g., an antibody).
  • Useful electrophilic groups on an antibody for that purpose include, but are not limited to, aldehyde and ketone carbonyl groups.
  • the heteroatom of a nucleophilic group of a Stretcher Unit precursor can react with an electrophilic group on an antibody and form a covalent bond to the antibody.
  • Useful nucleophilic groups on a Stretcher Unit precursor for that purpose include, but are not limited to, hydrazide, hydroxylamine, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide.
  • the electrophilic group on an antibody provides a convenient site for antibody attachment to form a Ligand-Drug Conjugate compound or Ligand Unit-Linker intermediate compound.
  • a sulfur atom of a Ligand Unit is bound to a succinimide ring system of a Stretcher Unit formed by reaction of a thiol functional group of a targeting ligand with a maleimide moiety of the corresponding Stretcher Unit precursor.
  • a thiol functional group of a Ligand Unit reacts with an alpha haloacetamide moiety to provide a sulfur-bonded Stretcher Unit by nucleophilic displacement of its halogen substituent.
  • Illustrative Stretcher Units prior to conjugation to the Ligand Unit comprise a maleimide moiety and are represented by structures including that of formula Z'a wherein the wavy line adjacent the carbonyl carbon atom indicates attachment to B, A, or S * , in the formulae above, depending on the presence or absence of A and/or B, R 17 is –(CH 2 ) 1-5 – or –CH 2 CH 2 (OCH 2 CH 2 ) 1-36 –.
  • R 17 is -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, –CH 2 CH 2 OCH 2 CH 2 -, –CH 2 CH 2 (OCH 2 CH 2 ) 2 –, –CH 2 CH 2 (OCH 2 CH 2 ) 3 –, –CH 2 CH 2 (OCH 2 CH 2 ) 4 –, –CH 2 CH 2 (OCH 2 CH 2 ) 5 –, –CH 2 CH 2 (OCH 2 CH 2 ) 6 –, –CH 2 CH 2 (OCH 2 CH 2 ) 7 –, –CH 2 CH 2 (OCH 2 CH 2 ) 8 –, –CH 2 CH 2 (OCH 2 CH 2 ) 10 –, –CH 2 CH 2 (OCH 2 CH 2 ) 12 –, –CH 2 CH 2 (OCH 2 CH 2 ) 14 –, –CH 2 CH 2
  • Stretcher Unit precursors comprises a maleimide moiety and are represented by structures including that of formula Z'a-BU wherein the wavy line adjacent the carbonyl carbon atom indicates attachment to B, A, or S * , in the formulae above, depending on the presence or absence of A and/or B, R 17 is R 17 is –(CH 2 ) 1-5 – or –CH 2 CH 2 (OCH 2 CH 2 ) 1-5 –, substituted with a Basic Unit (BU), such as an optionally substituted aminoalkyl, e.g., –(CH 2 ) x NH 2 , –(CH 2 ) x NHR a , and –(CH 2 ) x N(R a ) 2 , wherein subscript x is an integer of from 1-4, preferably R 17 is -CH 2 - or -CH 2 CH 2 - and subscript x is an integer of from 1-4, preferably R 17 is -CH 2 - or -CH 2 CH 2 -
  • a Stretcher Unit precursor (Z') is represented by one of the following structures: , wherein the wavy line adjacent to the carbonyl is as defined for Z'a or Z'a-BU.
  • the Stretcher unit precursor (Z') comprises a maleimide moiety and is represented by the structure of: , wherein the wavy line adjacent to the carbonyl is as defined for Z'a and the amino group is optional protonated or protected by an amino protecting group.
  • Stretcher Units having a BU moiety it will be understood that the amino functional group of that moiety is typically protected by an amino protecting group during synthesis, e.g., an acid labile protecting group (e.g., BOC).
  • an amino protecting group e.g., an acid labile protecting group (e.g., BOC).
  • Illustrative Stretcher Unit precursors covalently attached to a Connector Unit that comprise the structure of Z'a or Z'a-BU in which –R 17 - or –R 17 (BU)- is –CH 2 -, -CH 2 CH 2 - or –CH(CH 2 NH 2 )- have the following structures:
  • Stretcher Unit precursors bonded a Connector Unit have the structures above wherein A in any one of the above Z'-A- and Z'(BU)-A- structures is replaced by a Parallel Connector Unit and Partitioning Agent (-B(S * )-) having the structure of , wherein subscript m ranges from 1 to 6; n ranges from 8 to 24; R PEG is a PEG Capping Unit , preferably H, –CH 3 , or –CH 2 CH 2 CO 2 H, the asterisk (*) indicates covalent attachment to the Stretcher Unit precursor corresponding in structure to formula Z'a and the wavy line indicates covalent attachment to RL.
  • the shown PEG group is meant to be exemplary of a variety of Partitioning Agents including PEG groups of different lengths and other Partitioning Agents that are directly attached or modified for attachment to the Parallel Connector Unit.
  • the Stretcher Unit has a mass of no more than about 1000 daltons, no more than about 500 daltons, no more than about 200 daltons, from about 30, 50 or 100 daltons to about 1000 daltons, from about 30, 50 or 100 daltons to about 500 daltons, or from about 30, 50 or 100 daltons to about 200 daltons. 4.
  • a Connector Unit (A) is included in a Drug-Linker Compound in instances where it is desirable to add additional distance between the Stretcher Unit precursor (Z') and the Releasable Linker. In some embodiments, the extra distance will aid with activation within RL. Accordingly, the Connector Unit (A), when present, extends the framework of the Linker Unit. In that regard, a Connector Unit (A) is covalently bonded with the Stretcher Unit (or its precursor) at one terminus and is covalently bonded to the optional Parallel Connector Unit or the Partitioning Agent (S * ) at its other terminus.
  • the Connector Unit is any group that serves to provide for attachment of the Releasable Linker to the remainder of the Linker Unit (Q).
  • the Connector Unit can, for example, comprise one or more (e.g., 1-10, preferably, 1, 2, 3, or 4) proteinogenic or non-proteinogenic amino acid, amino alcohol, amino aldehyde, diamino residues.
  • the Connector Unit is a single proteinogenic or non- proteinogenic amino acid, amino alcohol, amino aldehyde, or diamino residue.
  • An exemplary amino acid capable of acting as Connector units is ⁇ -alanine.
  • a representative Connector Unit having a carbonyl group for attachment to the Partitioning Agent (S * ) or to –B(S * )- is as follows: , wherein in each instance R 13 is independently selected from the group consisting of –CH 2 CH 2 (OCH 2 CH 2 ) k –, -C 1 -C 6 alkylene-, -C 3 -C 8 carbocyclo-, -arylene-, -C 1 -C 10 heteroalkylene-, -C 3 -C 8 heterocyclo-, -C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, -C 1 - C 10 alkylene-(C 3 -C 8 carbocyclo)-, -(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, and -(C
  • R 13 is -C 1 -C 6 alkylene and c is 1.
  • Another representative Connector Unit having a carbonyl group for attachment to Partitioning Agent (S * ) or to –B(S * )- is as follows: , wherein R 13 is –CH 2 CH 2 (OCH 2 CH 2 ) k –, -C 1 -C 6 alkylene-, -C 3 -C 8 carbocyclo-, -arylene-, -C 1 -C 10 heteroalkylene-, -C 3 -C 8 heterocyclo-, -C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, -C 1 - C 10 alkylene-(C 3 -C 8 carbocyclo)-, -(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)
  • R 13 is -C 1 -C 6 alkylene.
  • a representative Connector Unit having a NH moiety that attaches to Partitioning Agent (S * ) or to –B(S * )- is as follows: , wherein in each instance, R 13 is independently selected from the group consisting of –CH 2 CH 2 (OCH 2 CH 2 ) k –, -C 1 -C 6 alkylene-, -C 3 -C 8 carbocyclo-, -arylene-, -C 1 -C 10 heteroalkylene-, -C 3 -C 8 heterocyclo-, -C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, -(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene alkylene
  • R 13 is -C 1 -C 6 alkylene and subscript c is 1.
  • Another representative Connector Unit having a NH moiety that attaches to Partitioning Agent (S * ) or to –B(S * )- is as follows: , wherein R 13 is –CH 2 CH 2 (OCH 2 CH 2 )k–, -C 1 -C 6 alkylene-, -C 3 -C 8 carbocyclo-, -arylene-, -C 1 - C 10 heteroalkylene-, -C 3 -C 8 heterocyclo-, -C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, -(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene- (C 3 -C 8 carbocycl
  • Connector Units include those having the following structure of: , wherein the wavy line adjacent to the nitrogen indicates covalent attachment a Stretcher Unit (Z) (or its precursor Z'), and the wavy line adjacent to the carbonyl indicates covalent attachment to Partitioning Agent (S * ) or to –B(S * )-; and m is an integer ranging from 1 to 6, preferably 2 to 6, more preferably 2 to 4. 5.
  • Releasable Linker (RL) [0326] The Releasable Linker (RL) is capable of linking to the Spacer Unit (Y) or the Drug Unit (D).
  • RL comprises a cleavable bond (i.e., a reactive site) that upon action by an enzyme present within a hyper-proliferating cell or hyper-activated immune cells or characteristic of the immediate environment of these abnormal or unwanted cells, or upon non-enzymatic action due to conditions more likely experienced by hyper-proliferating cells in comparison to normal cells, releases free drug.
  • RL comprises a cleavable bond that is more likely acted upon intracellularly in a hyper-proliferating cell or hyper- activated immune cell due to preferential entry into such cells in comparison to normal cells.
  • Peptide Releasable Linkers [0327] In some embodiments, the Releasable Linker is a Peptide Releasable Linker.
  • the Peptide Releasable Linker will comprise one or more contiguous or non-contiguous sequences of amino acids (e.g., so that RL has 1 to no more than 12 amino acids).
  • the Peptide Releasable Linker can comprise or consist of, for example, an amino acid, a dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit.
  • an amide linkage between the amino acids is cleaved, which ultimately leads to release of free drug.
  • an enzyme e.g., a tumor-associated protease
  • an amide linkage between the amino acids is cleaved, which ultimately leads to release of free drug.
  • Each amino acid is proteinogenic or non-proteinogenic and/or a D- or L-isomer provided that RL comprises a cleavable bond that, when cleaved, initiates release of the Drug Unit.
  • the Peptide Releasable Linker will comprise only proteinogenic amino acids.
  • the Peptide Releasable Linker will have from 1 to no more than 12 amino acids in contiguous sequence.
  • each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, selenocysteine, ornithine, penicillamine, ⁇ -alanine, aminoalkanoic acid, aminoalkynoic acid, aminoalkanedioic acid, aminobenzoic acid, amino- heterocyclo-alkanoic acid, heterocyclo-carboxylic acid, citrulline, statine, diaminoalkanoic acid, and derivatives thereof.
  • each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, and selenocysteine.
  • each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, and valine.
  • each amino acid is selected from the proteinogenic or the non- proteinogenic amino acids.
  • each amino acid is independently selected from the group consisting of the following L-(proteinogenic) amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan and valine.
  • L-(proteinogenic) amino acids alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan and valine.
  • each amino acid is independently selected from the group consisting of the following D-isomers of these proteinogenic amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan and valine.
  • the Peptide Releasable Linker comprises only proteinogenic amino acids. In other embodiments, the Peptide Releasable Linker comprises only non-proteinogenic amino acids.
  • the Peptide Releasable Linker comprises a proteinogenic amino acid attached to a non-proteinogenic amino acid. In some embodiments, Peptide Releasable Linker comprises a proteinogenic amino acid attached to a D-isomer of a proteinogenic amino acid.
  • each amino acid is independently selected from the group consisting of ⁇ -alanine, N-methylglycine, glycine, lysine, valine and phenylalanine.
  • Exemplary Peptide Releasable Linkers include dipeptides or tripeptides with-Val- Lys-Gly-, -Val-Cit-, -Phe-Lys- or –Val-Ala-.
  • Useful Peptide Releasable Linkers are designed and optimized in their selectivity for enzymatic cleavage by a particular enzyme, for example, a tumor-associated protease. In some embodiments, cleavage of a linkage is catalyzed by cathepsin B, C or D, or a plasmin protease.
  • the Peptide Releasable Linker (RL) will be represented by -(–AA-) 1-12 -, or (–AA-AA-) 1-6 wherein AA is at each occurrence independently selected from proteinogenic or non-proteinogenic amino acids. In one aspect, AA is at each occurrence independently selected from proteinogenic amino acids.
  • RL is a tripeptide having the formula: AA1-AA2- AA3, wherein AA1, AA2 and AA3 are each independently an amino acid and wherein AA 1 attaches to –NH- and AA 3 attaches to S*.
  • AA3 is gly or ⁇ -ala.
  • each R 19 is independently hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH 2 ) 3 NH 2 , or -(CH 2 ) 4 NH 2 . In some aspects, each R 19 is independently hydrogen, isopropyl, or -(CH 2 ) 4 NH 2 .
  • RL comprises a peptide selected from the group consisting of gly-gly, gly-gly-gly, gly-gly-gly-gly, val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe- lys-gly, leu-lys-gly, gly-val-lys-gly, val-lys-gly-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu- leu-gly, gly-gly-phe-gly, gly-gly-phe-gly-gly, val-gly, and val-lys- ⁇ -ala.
  • RL comprises a peptide selected from the group consisting of gly-gly-gly, gly-gly-gly-gly, val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, gly-val-lys-gly, val-lys-gly-gly, val-lys-ala, val-lys-leu, leu-leu-gly, gly-gly-phe-gly, and val-lys- ⁇ -ala.
  • RL comprises a peptide selected from the group consisting of gly-gly-gly, val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu- lys-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly and val-lys- ⁇ -ala.
  • RL comprises a peptide selected from the group consisting of gly-gly-gly-gly, gly-val-lys-gly, val-lys-gly-gly, and gly-gly-phe-gly.
  • RL is a peptide selected from the group consisting of val- gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly and val-lys- ⁇ -ala.
  • RL is val-lys-gly.
  • RL is val-lys- ⁇ -ala.
  • Glycoside Unit Releasable Linkers [0348] In some embodiments, the Releasable Linker is a Glycoside (e.g., Glucuronide) Unit.
  • a self-immolation cascade is activated by operation of a glycosidase on a carbohydrate moiety of the Glycoside (e.g., Glucuronide) Unit.
  • Glycoside e.g., Glucuronide
  • a number of sugars are useful in the embodiments described herein.
  • Particular carbohydrate moieties include those of Galactose, Glucose, Mannose, Xylose, Arabinose, Mannose-6-phosphate, Fucose, Rhamnose, Gulose, Allose, 6-deoxy-glucose, Lactose, Maltose, Cellobiose, Gentiobiose, Maltotriose, GlcNAc, GalNAc and maltohexaose.
  • a Glycoside (e.g., Glucuronide) Unit typically comprises a sugar moiety (Su) linked via an oxygen glycosidic bond to a self-immolative spacer. Cleavage of the oxygen glycosidic bond initiates the self-immolation reaction sequence that result in release of free drug.
  • the self-immolation sequence is activated from cleavage by ⁇ - glucuronidase of a Glycoside (e.g., Glucuronide) Unit, which is an exemplary glycoside unit.
  • the Glycoside (e.g., Glucuronide) Unit comprises an activation unit and a self-immolative Spacer Unit.
  • the Glycoside (e.g., Glucuronide) Unit comprises a sugar moiety (Su) linked via an oxygen glycosidic bond to a self-immolative Spacer Unit.
  • a Glycoside (e.g., Glucuronide) Unit comprises a sugar moiety (Su) linked via an oxygen glycoside bond (-O'-) to a Self-immolative Unit (SP) of the formula: wherein the wavy lines indicate covalent attachment to the Drug Unit or to a Spacer Unit that is attached to the Drug Unit, and to the Stretcher Unit precursor (Z'), either directly or indirectly through the Connector Unit (A) or Parallel Connector Unit (B), Partitioning Agent (S * ) or combinations of the Connector Unit and Parallel Connector Unit, as the case may be.
  • the oxygen glycosidic bond (-O'-) is typically a ⁇ -glucuronidase-cleavage site (i.e., Su is from glucuronide), such as a glycoside bond cleavable by human, lysosomal ⁇ - glucuronidase.
  • the Glycoside (e.g., Glucuronide) Unit is represented by formula Ga, Gb, or Gc:
  • Su is a Sugar moiety, -O'- represents an oxygen glycosidic bond;
  • R 1S , R 2S and R 3S independently are hydrogen, a halogen, -CN,-NO 2 , or other electron withdrawing group, or an electron donating group;
  • R BZ is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, a PEG unit, a cyclodextrin unit, a polyamide, a hydrophilic peptide, a polysaccharide, and a dendrimer; and wherein the wavy line indicates attachment to a Stretcher Unit precursor (Z'), either directly or indirectly through a Connector Unit or Parallel Connector Unit or Connector unit and Parallel Connector Unit); and # indicates attachment to the Drug Unit or to a Spacer (either directly or indirectly via an intervening functional group or other moiety).
  • R 1S , R 2S , and R 3S are independently selected from hydrogen, halogen, -CN, or -NO 2 . In some embodiments, R 1S , R 2S and R 3S are each hydrogen. In some embodiments, R 2S is an electron withdrawing group, preferably NO 2 , and R 1S and R 3S are each hydrogen.
  • the activatable self-immolative group capable of glycosidase cleavage to initiate the self-immolative reaction sequence is represented by the formula Gd: wherein R 4S is CH 2 OH or –CO 2 H, the wavy line indicates covalent attachment to a Stretcher Unit (Z) (or its precursor Z'), either directly or indirectly through a Connector Unit or Parallel Connector Unit or Connector unit and Parallel Connector Unit, and the hash mark (#) indicates covalent attachment to the methylene carbamate unit.
  • the activatable self-immolative moiety comprises a Glycoside (e.g., Glucuronide) Unit
  • a Glycoside e.g., Glucuronide
  • Ge the following formula Ge: wherein the wavy line indicates covalent attachment to a Stretcher Unit (Z) (or its precursor Z'), either directly or indirectly through a Connector Unit or Parallel Connector Unit or Connector unit and Parallel Connector Unit and the hash mark (#) indicates covalent attachment of the benzylic carbon of a Spacer or functional group attached to the Drug Unit.
  • the structure of formula Ge is attached to the Drug Unit via a quaternized tertiary amine (N + ), wherein the nitrogen atom is from a tertiary amine functional group on the unconjugated Drug Unit.
  • Another type of Releasable Linker that provides a mechanism for separation of the Drug Unit from the Ligand Unit and other components of the Linker Unit through activation of a self-immolation cascade within the Linker Unit comprises a p-aminobenzyloxycarbonyl (PAB) moiety whose phenylene component is substituted with Jm wherein the subscript m indicating the number of substituents is an integer ranging from 0-4, and each J is independently -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -halogen, -nitro or -cyano.
  • PAB p-aminobenzyloxycarbonyl
  • RL is a self-immolative group capable of releasing -D without the need for a separate hydrolysis step or subsequent self-immolative event.
  • -RL- is a PAB moiety that is linked to the carbonyl of -W- via the amino nitrogen atom of the PAB group, and connected directly to -D via a carbonate group.
  • -RL- comprises a PAB moiety that is linked to the carbonyl of -A-, -S * - or –B- via the amino nitrogen atom of the PAB group, and connected directly to -D via a carbonate group.
  • RL units containing a PAB moiety are represented by the formula: , wherein subscript m is an integer ranging from 0-4, and each J is independently -C 1 -C 8 alkyl, -O-(C 1 -C 8 alkyl), -halogen, -nitro or –cyano.
  • self-immolative groups include, but are not limited to, aromatic compounds that are electronically similar to the PAB moiety such as 2-aminoimidazol-5- methanol derivatives (Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and ortho or para- aminobenzylacetals.
  • Other RLs undergo cyclization upon amide bond hydrolysis, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al., Chemistry Biology, 1995, 2, 223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm, et al., J. Amer. Chem.
  • RL is a branched bis(hydroxymethyl)styrene (BHMS) unit.
  • BHMS branched bis(hydroxymethyl)styrene
  • RL has the formula: wherein the wavy line marked with ** indicates the site of attachment to D; and the wavy line marked with * indicates the point of attachment to additional linker components of Q.
  • a PAB-containing RL is directly attached to the Drug Unit. 6.
  • the Ligand-Drug Conjugates described herein can also include a Partitioning Agent (S * ).
  • the Partitioning Agent portions are useful, for example, to mask the hydrophobicity of particular Drug Units or Linking Unit components.
  • Representative Partitioning Agents include polyethylene glycol (PEG) units, cyclodextrin units, polyamides, hydrophilic peptides, polysaccharides and dendrimers.
  • the groups may be present as an ‘in line’ component or as a side chain or branched component.
  • the Linker Units can include a lysine residue (or Parallel Connector Unit, B) that provides simple functional conjugation of, for example, the PEG unit, to the remainder of the Linking Unit.
  • Polyethylene Glycol (PEG) Unit When present, polydisperse PEGs, monodisperse PEGs, and discrete PEGs are used as part of the Partitioning Agents in Compounds of the present invention. Polydisperse PEGs are a heterogeneous mixture of sizes and molecular weights whereas monodisperse PEGs are typically purified from heterogeneous mixtures and are therefore provide a single chain length and molecular weight.
  • Preferred PEG Units are discrete PEGs, compounds that are synthesized in stepwise fashion and not via a polymerization process. Discrete PEGs provide a single molecule with defined and specified chain length.
  • the PEG Unit provided herein can comprise one or multiple polyethylene glycol chains.
  • a polyethylene glycol chain is composed of at least two ethylene oxide (CH 2 CH 2 O) subunits.
  • the polyethylene glycol chains are linked together, for example, in a linear, branched or star shaped configuration.
  • at least one of the PEG chains is derivitized at one end for covalent attachment to an appropriate site on a component of the Linker Unit (e.g. B) or is used as an in-line (e.g., bifunctional) linking group within to covalently join two of the Linker Unit components (e.g., Z-A-S * -RL- , Z-A-S * -RL-Y- ).
  • Exemplary attachments within the Linker Unit are by means of non-conditionally cleavable linkages or via conditionally cleavable linkages. Exemplary attachments are via amide linkage, ether linkages, ester linkages, hydrazone linkages, oxime linkages, disulfide linkages, peptide linkages or triazole linkages. In some embodiments, attachment within the Linker Unit is by means of a non-conditionally cleavable linkage. In some embodiments, attachment within the Linker Unit is not via an ester linkage, hydrazone linkage, oxime linkage, or disulfide linkage. In some embodiments, attachment within the Linker Unit is not via a hydrazone linkage.
  • a conditionally cleavable linkage refers to a linkage that is not substantially sensitive to cleavage while circulating in the plasma but is sensitive to cleavage in an intracellular or intratumoral environment.
  • a non-conditionally cleavable linkage is one that is not substantially sensitive to cleavage in any biological environment.
  • Chemical hydrolysis of a hydrazone, reduction of a disulfide, and enzymatic cleavage of a peptide bond or glycosidic linkage are examples of conditionally cleavable linkages.
  • the PEG Unit is directly attached to a Parallel Connector Unit B, wherein the other terminus (or termini) of the PEG Unit is free and untethered and may take the form of a methoxy, carboxylic acid, alcohol or other suitable functional group.
  • the methoxy, carboxylic acid, alcohol or other suitable functional group acts as a cap for the terminal PEG subunit of the PEG Unit.
  • untethered it is meant that the PEG Unit will not be attached at that untethered site to a Drug Unit, to an antibody, or to another linking component.
  • the PEG Unit in addition to comprising repeating ethylene glycol subunits may also contain non-PEG material (e.g., to facilitate coupling of multiple PEG chains to each other).
  • Non-PEG material refers to the atoms in the PEG Unit that are not part of the repeating -CH 2 CH 2 O- subunits.
  • the PEG Unit comprises two monomeric PEG chains attached to each other via non-PEG elements.
  • the PEG Unit comprises two linear PEG chains attached to a central core or Parallel Connector Unit (i.e., the PEG Unit itself is branched).
  • WO 90/12874 PEGylation of erythropoietin containing a recombinantly introduced cysteine residue using a cysteine-specific mPEG derivative
  • U.S. Pat. No. 5,757,078 PEGylation of EPO peptides
  • U.S. Pat. No. 5,672,662 Poly(ethylene glycol) and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications
  • U.S. Pat. No. 6,077,939 PEGylation of an N-terminal .alpha.-carbon of a peptide
  • PEG may be covalently bound to amino acid residues via a reactive group.
  • Reactive groups are those to which an activated PEG molecule may be bound (e.g., a free amino or carboxyl group).
  • N-terminal amino acid residues and lysine (K) residues have a free amino group; and C-terminal amino acid residues have a free carboxyl group.
  • Thiol groups e.g., as found on cysteine residues
  • enzyme-assisted methods for introducing activated groups e.g., hydrazide, aldehyde, and aromatic-amino groups
  • activated groups e.g., hydrazide, aldehyde, and aromatic-amino groups
  • PEG molecules may be attached to amino groups using methoxylated PEG ("mPEG”) having different reactive moieties.
  • mPEG methoxylated PEG
  • reactive moieties include succinimidyl succinate (SS), succinimidyl carbonate (SC), mPEG-imidate, para-nitrophenylcarbonate (NPC), succinimidyl propionate (SPA), and cyanuric chloride.
  • Non-limiting examples of such mPEGs include mPEG-succinimidyl succinate (mPEG-SS), mPEG2-succinimidyl succinate (mPEG2-SS); mPEG-succinimidyl carbonate (mPEG-SC), mPEG2-succinimidyl carbonate (mPEG2-SC); mPEG-imidate, mPEG-para-nitrophenylcarbonate (mPEG-NPC), mPEG-imidate; mPEG 2 -para- nitrophenylcarbonate (mPEG2-NPC); mPEG-succinimidyl propionate (mPEG-SPA); mPEG2- succinimidyl propionate (mPEG2-SPA); mPEG-N-hydroxy-succinimide (mPEG-NHS); mPEG 2 -N-hydroxy-succinimide (mPEG 2 -NHS); mPEG-cyanuri
  • the PEG Unit is functionalized so that it is capable of covalent attachment to other Linker Unit components.
  • Functionalization includes, for example, via an amine, thiol, NHS ester, maleimide, alkyne, azide, carbonyl, or other functional group.
  • the PEG Unit further comprises non-PEG material (i.e., material does not comprise -CH 2 CH 2 O-) that provides coupling to other Linker Unit components or to facilitate coupling of two or more PEG chains.
  • the presence of the PEG Unit (or other Partitioning Agent) in the Linker Unit can have two potential impacts upon the pharmacokinetics of the resulting Ligand-Drug Conjugate.
  • the desired impact is a decrease in clearance (and consequent increase in exposure) that arises from the reduction in non-specific interactions induced by the exposed hydrophobic elements of the Ligand-Drug Conjugate or to the Drug Unit itself.
  • the second impact is undesired and is a decrease in volume and rate of distribution that sometimes arises from the increase in the molecular weight of the Ligand-Drug Conjugate.
  • Increasing the number of PEG subunits increases the hydrodynamic radius of a conjugate, typically resulting in decreased diffusivity.
  • the PEG Unit comprises one or more linear PEG chains each having at least 2 subunits, at least 3 subunits, at least 4 subunits, at least 5 subunits, at least 6 subunits, at least 7 subunits, at least 8 subunits, at least 9 subunits, at least 10 subunits, at least 11 subunits, at least 12 subunits, at least 13 subunits, at least 14 subunits, at least 15 subunits, at least 16 subunits, at least 17 subunits, at least 18 subunits, at least 19 subunits, at least 20 subunits, at least 21 subunits, at least 22 subunits, at least 23 subunits, or at least 24 subunits.
  • the PEG Unit comprises a combined total of at least 4 subunits, at least 6 subunits, at least 8 subunits, at least 10 subunits, or at least 12 subunits. In some such embodiments, the PEG Unit comprises no more than a combined total of about 72 subunits, preferably no more than a combined total of about 36 subunits.
  • the PEG Unit comprises one or more linear PEG chains each having 2 subunits, 3 subunits, 4 subunits, 5 subunits, 6 subunits, 7 subunits, 8 subunits, 9 subunits, 10 subunits, 11 subunits, 12 subunits, 13 subunits, 14 subunits, 15 subunits, 16 subunits, 17 subunits, 18 subunits, 19 subunits, 20 subunits, 21 subunits, 22 subunits, 23 subunits, or 24 subunits.
  • the PEG Unit comprises a combined total of 4 subunits, 6 subunits, 8 subunits, 10 subunits, or 12 subunits.
  • the PEG Unit comprises no more than a combined total of about 72 subunits, preferably no more than a combined total of about 36 subunits.
  • the PEG Unit comprises a combined total of from 4 to 72, 4 to 60, 4 to 48, 4 to 36 or 4 to 24 subunits, from 5 to 72, 5 to 60, 5 to 48, 5 to 36 or 5 to 24 subunits, from 6 to 72, 6 to 60, 6 to 48, 6 to 36 or from 6 to 24 subunits, from 7 to 72, 7 to 60, 7 to 48, 7 to 36 or 7 to 24 subunits, from 8 to 72, 8 to 60, 8 to 48, 8 to 36 or 8 to 24 subunits, from 9 to 72, 9 to 60, 9 to 48, 9 to 36 or 9 to 24 subunits, from 10 to 72, 10 to 60, 10 to 48, 10 to 36 or 10 to 24 subunits, from 11 to 72, 11 to 60, 11 to 48, 11 to 36 or 11 to 24 subunits,
  • the Partitioning Agent S* is a linear PEG Unit comprising from 2 to 20, or from 2 to 12, or from 4 to 12, or 4, 8, or 12 -CH 2 CH 2 O- subunits.
  • the linear PEG Unit is connected at one end of the PEG Unit to the RL Unit and at the other end of the PEG Unit to the Stretcher/Connector Units (Z-A-).
  • the PEG Unit is connected to the RL Unit via a -CH 2 CH 2 C(O)- group that forms an amide bond with the RL Unit (e.g., -(CH 2 CH 2 O) n -CH 2 CH 2 C(O)-RL) and to the Stretcher Unit/Connector Unit (Z-A-) via an -NH- group (e.g., Z-A-NH-(CH 2 CH 2 O)n-) that forms an amide bond with the Z-A- portion.
  • a -CH 2 CH 2 C(O)- group that forms an amide bond with the RL Unit
  • Z-A- Stretcher Unit/Connector Unit
  • PEG Units that are connected to the RL and Stretcher/Connector Units (Z-A-) are shown below:
  • the PEG Unit is: , wherein the wavy line on the left indicates the site of attachment to Z-A-, the wavy line on the right indicates the site of attachment to RL, and each b is independently selected from 2 to 72, 4 to 72, 6 to 72, 8 to 72, 10 to 72, 12 to 72, 2 to 24, 4 to 24, 6 to 24, or 8 to 24, 2 to 12, 4 to 12, 6 to 12, and 8 to 12.
  • subscript b is 2, 4, 8, 12, or 24.
  • subscript b is 2.
  • subscript b is 4.
  • subscript b is 8. In some embodiments, subscript b is 12. [0381] In some embodiments, the linear PEG Unit that is connected to the Parallel Connector Unit at one end and comprises a terminal cap at the other end. In some embodiments, the PEG Unit is connected to the Parallel Connector Unit via a carbonyl group that forms an amide bond with the Parallel Connector Unit lysine residue amino group (e.g., – CH 2 CH 2 (OCH 2 CH 2 ) k –C(O)-B-, wherein k is an integer from 1 to 36) and includes a PEG Unit terminal cap group selected from the group consisting of C 1-4 alkyl and C 1-4 alkyl-CO 2 H.
  • a carbonyl group that forms an amide bond with the Parallel Connector Unit lysine residue amino group (e.g., – CH 2 CH 2 (OCH 2 CH 2 ) k –C(O)-B-, wherein k is an integer from 1 to 36) and includes a PEG Unit
  • the Partitioning Agent S* is a linear PEG Unit comprising 4, 8, or 12 - CH 2 CH 2 O- subunits and a terminal methyl cap.
  • Illustrative linear PEG Units that are used in any of the embodiments provided herein are as follows: and in a particular embodiment, the PEG Unit is: wherein the wavy line indicates site of attachment to the Parallel Connector Unit (B), and each n is independently selected from 4 to 72, 6 to 72, 8 to 72, 10 to 72, 12 to 72, 6 to 24, or 8 to 24.
  • subscript b is about 4, about 8, about 12, or about 24.
  • PEG2 refers to specific embodiments of PEG Unit which comprises the number of PEG subunits (i.e., the number of subscription “b”).
  • PEG2 refers to embodiments of PEG Unit that comprises 2 PEG subunits
  • PEG4 refers to embodiments of PEG Unit that comprises 4 PEG subunits
  • PEG8 refers to embodiments of PEG Unit that comprises 8 PEG subunits
  • PEG12 refers to embodiments of PEG Unit that comprises 12 PEG subunits.
  • the PEG unit is selected such that it improves clearance of the resultant Ligand-Drug Conjugate but does not significantly impact the ability of the Conjugate to penetrate into the tumor.
  • the PEG unit to be selected for use will preferably have from 2 subunits to about 24 subunits, from 4 subunits to about 24 subunits, more preferably about 4 subunits to about 12 subunits.
  • the PEG Unit is from about 300 daltons to about 5 kilodaltons; from about 300 daltons, to about 4 kilodaltons; from about 300 daltons, to about 3 kilodaltons; from about 300 daltons, to about 2 kilodaltons; or from about 300 daltons, to about 1 kilodalton.
  • the PEG Unit has at least 6 subunits or at least 8, 10 or 12 subunits.
  • the PEG Unit has at least 6 subunits or at least 8, 10 or 12 subunits but no more than 72 subunits, preferably no more than 36 subunits.
  • the number of subunits can represent an average number, e.g., when referring to a population of Ligand-Drug Conjugates or Drug-Linker Compounds, and/or using polydisperse PEGs.
  • the Ligand-Drug Conjugates and Drug-Linker Compounds will comprise a Parallel Connector Unit to provide a point of attachment to a Partitioning Agent (shown in the Linker Units as -B(S * )-).
  • the PEG Unit is attached to a Parallel Connector Unit such as lysine as shown below wherein the wavy line and asterisks indicate covalent linkage within the Linker Unit of a Ligand-Drug Conjugate or Drug-Linker Compound: .
  • the Parallel Connector Unit (B) and Partitioning Agent (S*) (together, -B(S * )-) have the structure of wherein m ranges from 0 to 6; n ranges from 2 to 24; R PEG is a PEG Capping Unit, preferably H, –CH 3 , or –CH 2 CH 2 CO 2 H, the asterisk (*) indicates covalent attachment to a Connector Unit A corresponding in formula Za, Za', Zb' or Zc' and the wavy line indicates covalent attachment to the Releasable Linker (RL).
  • the structure is attached to a Connector Unit A in formula Za or Za’.
  • n is 2, 4, 8, or 12.
  • the shown PEG group is meant to be exemplary of a variety of Partitioning Agents including PEG groups of different lengths and other Partitioning Agents that are directly attached or modified for attachment to the Parallel Connector Unit.
  • Spacer Unit Y
  • the Ligand-Drug Conjugates provided herein will have a Spacer (Y) between the Releasable Linker (RL) and the Drug Unit.
  • the Spacer Unit is a functional group to facilitate attachment of RL to the Drug Unit, or provides additional structural components to further facilitate release of the Drug Unit from the remainder of the Conjugate (e.g., a methylene carbamate unit or a self-immolative para-aminobenzyl (PAB) component).
  • the Spacer Unit Y is represented by one of the following formulae: wherein EWG represents an electron-withdrawing group and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof.
  • the Spacer Unit-Drug Unit group (–Y-T*-D) is represented by one of the following formulae: wherein the wavy line adjacent is the point of covalent attachment to RL, T* is as defined above, and D' represents the remainder of the Drug Unit, wherein T* and D' together form a Drug Unit of Formula (Ia), or any subformula thereof.
  • the Spacer Unit is represented by the formula: wherein the wavy line adjacent to the nitrogen atom is the point of covalent attachment to RL, as defined above, and the wavy line next to the benzylic carbon atom connects to a Drug Unit.
  • the Drug Unit is attached to the benzylic carbon atom via a quaternized tertiary amine (N+) of D.
  • the Spacer Unit is represented by the formula: wherein the wavy line adjacent to the nitrogen atom is the point of covalent attachment to RL, as defined above, and the wavy line next to the -OC(O)- group connects to a Drug Unit.
  • the Drug Unit is attached via a primary or secondary amine.
  • Ligand-Drug Conjugate compounds [0395] In context of Ligand-Drug Conjugate compounds – the assembly is described by the component groups as described for Drug-Linker compounds, with the exception of the Stretcher Unit Z and the Ligand Unit L. The Stretcher Unit Z is coordinated to the Ligand Unit L in Ligand-Drug Conjugate compounds, as described below. While some procedures for the preparation of Ligand-Drug Conjugate compounds are described herein, the order of assembly and the general conditions to prepare the compounds will be well understood by one of skill in the art.
  • a Ligand-Drug Conjugate compound comprises an auristatin compound of Formula (I), or any subformula thereof, a Linker Unit (Q) comprising a Releasable Linker (RL) that is other than a Glycoside (e.g., Glucuronide) Unit through which the Ligand Unit is connected to the conjugated auristatin compound, and a Ligand Unit (L).
  • the Linker Unit comprises, in addition to RL, a Stretcher Unit (Z) connected to the Ligand Unit and is capable of (directly or indirectly) connecting the RL to the Ligand Unit.
  • a Parallel Connector Unit (B) is present when it is desired to add a Partitioning Agent (S * ) as a side chain appendage.
  • a Connector Unit (A) is present when it is desirable to add more distance between the Stretcher Unit and RL.
  • a Ligand-Drug Conjugate compound comprises an auristatin compound of Formula (I), or any subformula thereof, and a Linker Unit (Q), wherein Q comprises a Releasable Linker (RL) that is a Glycoside (e.g., Glucuronide) Unit, directly attached to a Stretcher Unit (Z) or indirectly to Z through attachment to intervening component(s) of the Ligand-Drug Conjugate compound’s Linker Unit (i.e., A, S * and/or B(S * )), wherein Z forms a covalent bond to a targeting agent (e.g., a Ligand Unit).
  • RL Releasable Linker
  • a Ligand-Drug Conjugate compound comprises an auristatin of Formula (I), or any subformula thereof, a Linker Unit (Q), wherein Q comprises a Releasable Linker (RL) that is other than a Glycoside (e.g., Glucuronide) Unit (RL), directly attached to a Stretcher Unit (Z) or indirectly to Z through attachment to intervening component(s) of the Ligand-Drug Conjugate compound’s Linker Unit (i.e., A, S * and/or B(S * )), wherein Z forms a covalent bond to a targeting agent (e.g., a Ligand Unit).
  • a targeting agent e.g., a Ligand Unit
  • the Ligand-Drug Conjugate compound has the formula: L-(Q-D) p or a pharmaceutically acceptable salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S * -RL-, (iv) Z'-A-S * -RL-Y-, (v) Z'-A-B(S * )-RL-, (vi) Z'-A-B(S * )-RL-Y-, (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-; Z' is a Stretcher Unit precursor; A is a Linker Unit selected from the group
  • Ligand-Drug Conjugate compounds of formula L-(Q-D)p wherein the Drug Unit D has Formula (Iz*): wherein X b is -NR 2 - # or -N + R 1 R 5 - # , wherein the # denotes the point of attachment to Q, and X a is or X a and X b are taken together with the carbon atom to which they are attached to form wherein the asterisk denotes the carbon atom of Formula (I) that bears the X a and X b groups, and the # denotes the point of attachment to Q; R 1 and R 5 are independently C 1 -C 4 alkyl; X is OH, -S(O) 2 R a , -S(O)-R a -S(O) 2 NR a R b , -NHS(O) 2 R a , or -NHC(O)R a ; R 2
  • the Ligand-Drug Conjugate compound has Formula (Ia*) or (Ia**): or a salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit as described above; p is an integer ranging from 1 to 12; and the remaining variables are as described for Drug-Linker moieties of Formula (Ia') or Formula (Ia'') above.
  • the Ligand-Drug Conjugate compound has Formula (Ib*) or (Ib**): or a salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit as described above; p is an integer ranging from 1 to 12; and the remaining variables are as described for Drug-Linker moieties of Formula (Ib') or Formula (Ib'') above.
  • the Ligand-Drug Conjugate compound has Formula (Ic*) or (Ic**): or a salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit as described above; p is an integer ranging from 1 to 12; and the remaining variables are as described for Drug-Linker moieties of Formula (Ic') or Formula (Ic'') above.
  • the Ligand-Drug Conjugate compound has Formula (Id*) or (Id**): or a salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit as described above; p is an integer ranging from 1 to 12; and the remaining variables are as described for Drug-Linker moieties of Formula (Id') or Formula (Id'') above.
  • the Ligand-Drug Conjugate compound has Formula (Ie*) or (Ie**): or a salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit as described above; p is an integer ranging from 1 to 12; and the remaining variables are as described for Drug-Linker moieties of Formula (Ie') or Formula (Ie'') above.
  • the Ligand-Drug Conjugate compound has Formula (If*) or (If**):
  • the component groups of the Ligand-Drug Conjugate compounds described are in many cases identical to the component groups for Drug-Linker compounds as described above, including A, B, S*, RL, W, Y, and D. It is to be understood that embodiments are contemplated wherein the Drug Unit D of the Ligand-Drug Conjugates described herein is conforms to the description of Formula (I'), or any subformula thereof. Other component groups are described below.
  • Stretcher Unit Z [0408] Representative Stretcher Units of such embodiments include those having the structures of:
  • R 17 is –CH 2 CH 2 (OCH 2 CH 2 ) k –, -C 1 -C 10 alkylene-, C 1 -C 10 heteroalkylene-, -C 3 -C 8 carbocyclo-, -O- (C 1 -C 8 alkylene)-, -arylene-, -C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, -(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, -C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, -C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, -C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, -C 3 -C 8
  • the R 17 group is optionally substituted by a Basic Unit (BU) such as an aminoalkyl moiety, e.g. –(CH 2 ) x NH 2 , –(CH 2 ) x NHR a , and –(CH 2 ) x NR a 2 , wherein subscript x is an integer of from 1-4 and each R a is independently selected from the group consisting of C 1-6 alkyl and C 1-6 haloalkyl, or two R a groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group.
  • BU Basic Unit
  • wavy line adjacent the carbonyl carbon atom indicates attachment to B, A, or S * , in the formulae above, depending on the presence or absence of A and/or B, and the other wavy line indicates covalent bonding of the succinimide ring carbon atom to a sulfur atom of a Ligand Unit.
  • a Ligand Unit-substituted succinimide may exist in hydrolyzed form(s). Those forms are exemplified below for hydrolysis of Za or Za-BU, wherein the structures representing the regioisomers from that hydrolysis have formula Zb and Zc or Zb-BU and Zc-BU.
  • a Stretcher unit (Z) comprises a succinic acid-amide moiety represented by the following: wherein the wavy line adjacent to the carbonyl carbon atom bonded to R 17 and the wavy line adjacent to the carbon atom of the succinic acid-amide moiety is as defined for Za or Za-BU, depending on the presence or absence of A and/or B; and R 17 is –C 1 -C 5 alkylene-, wherein in Zb-BU and Zc-BU the alkylene is substituted by a Basic Unit (BU), wherein BU is –(CH 2 )xNH 2 , –(CH 2 )xNHR a , or –(CH 2 )xN(R a ) 2 , wherein subscript x is an integer of from 1-4 and each R a is independently selected from the group consisting of C 1-6 alkyl and C 1-6 haloalkyl, or both R a together with the nitrogen to which they are attached define
  • -Z-A- comprises a moiety derived from a maleimido- alkanoic acid moiety or an mDPR moiety. See, for example, see WO 2013/173337.
  • Z-A- is derived from a maleimido-propionyl moiety.
  • a Stretcher unit (Z) comprises an succinic acid-amide moiety represented by the structure of formula Zb’, Zc’, (R/S)-Zb’-BU, (S)-Zb’-BU, (R/S)- Zc'-BU or (S)-Zc’-BU as follows:
  • a Stretcher unit (Z) comprises a succinimide moiety represented by the structure of . , which may be generated from a maleimido-amino-propionyl (mDPR) analog (a 3-amino-2- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid derivative), or comprises a succinic acid-amide moiety represented by the structure of: .
  • mDPR maleimido-amino-propionyl
  • Stretcher Units bonded to a Ligand Unit (L) and a Connector Unit (A) have the structures above wherein A in any one of the above -Za'-A-, -Za'(BU)-A-, -Za'-A-, - Za'(BU)-A-, -Zb'-A-, -Zb'(BU)-A-, -Zb'-A-, -Zb'(BU)-, -Zc'-A- and Zc'(BU)-A- structures is replaced by a Parallel Connector Unit having the structure of: , wherein subscript m ranges from 1 to 6; n ranges from 8 to 24; R PEG is a PEG Capping Unit, preferably H, –CH 3 , or –CH 2 CH 2 CO 2 H, the asterisk (*) indicates covalent attachment to a Stretcher Unit corresponding in structure to formula Za, Za', Zb' or Zc' and the wavy line indicates
  • the Stretcher Unit is attached to the Ligand Unit via a disulfide bond between a sulfur atom of the Ligand Unit and a sulfur atom of the Stretcher unit.
  • a representative Stretcher Unit of this embodiment is depicted within the square brackets of Formula Zb: wherein the wavy line indicates attachment to the Parallel Connector Unit (B) or Connector Unit (A) if B is absent or a Partitioning Agent (S * ), if A and B are absent and R 17 is –CH 2 CH 2 (OCH 2 CH 2 ) k –, -C 1 -C 10 alkylene-, C 1 -C 10 heteroalkylene-, -C 3 -C 8 carbocyclo-, -O- (C 1 -C 8 alkylene)-, -arylene-, -C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene-(C 3 -
  • the reactive group of a Stretcher Unit precursor contains a reactive site that can form a bond with a primary or secondary amino group of a Ligand Unit.
  • these reactive sites include, but are not limited to, activated esters such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates and isothiocyanates.
  • Stretcher Units of this embodiment are depicted within the square brackets of Formulas Zci, Zcii and Zciii: ), wherein the wavy line indicates attachment to the Parallel Connector Unit (B) or Connector Unit (A) if B is absent or a Partitioning Agent (S * ), if A and B are absent and R 17 is –CH 2 CH 2 (OCH 2 CH 2 )k–, -C 1 -C 10 alkylene-, C 1 -C 10 heteroalkylene-, -C 3 -C 8 carbocyclo-, -O- (C 1 -C 8 alkylene)-, -arylene-, -C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, -C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, -(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, -
  • the reactive group of the Stretcher Unit precursor contains a reactive nucleophile that is capable of reacting with an electrophile present on, or introduced to, a Ligand Unit.
  • a carbohydrate moiety on a targeting ligand is mildly oxidized using a reagent such as sodium periodate and the resulting electrophilic functional group (-CHO) of the oxidized carbohydrate is condensed with a Stretcher Unit precursor that contains a reactive nucleophile such as a hydrazide, an oxime, a primary or secondary amine, a hydrazine, a thiosemicarbazone, a hydrazine carboxylate, or an arylhydrazide such as those described by Kaneko, T.
  • Ligand-Drug Conjguate compound of Table 3 or a pharmaceutically acceptable salt thereof.
  • Ligand-Drug Conjugate compounds corresponding to the compounds of Table 3 but having a succinic acid-amide moiety in place of the succinimide moiety are contemplated. Table 3.
  • Ligand-Drug Conjugate compounds corresponding to the compounds of Table 3 but having a succinic acid-amide moiety in place of the succinimide moiety are contemplated. Table 3.
  • Subscript p represents the number of Drug Linker moieties on a Ligand Unit of an individual Ligand-Drug Conjugate compound and is an integer ranging from 1 to 16, 1 to 12, 1 to 10, or 1 to 8. In any of the embodiments herein, there are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 Drug Linker moieties conjugated to a Ligand Unit of an individual Ligand-Drug Conjugate compound.
  • any of the structures and descriptions as described herein represent a population of individual Ligand-Drug Conjugate compounds substantially identical except for the number of Drug-Linker moieties bound to each Ligand Unit (i.e., a Ligand-Drug Conjugate composition) so that subscript p represents the average number of Drug-Linker moieties bound to the Ligand Units of the Ligand-Drug Conjugate composition.
  • subscript p is a number ranging from 1 to about 16, 1 to about 12, 1 to about 10, or 1 to about 8, from 2 to about 16, 2 to about 12, 2 to about 10, or 2 to about 8.
  • p is about 2.
  • p is about 4.
  • p is about 8.
  • p is about 16. In some aspects, p is 2. In some aspects, p is 4. In some aspects, p is 8. In some aspects, p is 16. In some embodiments, the value of subscript p refers to the average drug loading as well as the drug loading of the predominate Ligand- Drug Conjugate compound in the composition. [0426] In some embodiments, conjugation will be via the reduced interchain disulfides and there will from 1 to about 8 Drug-Linker Compound molecules conjugated to a targeting agent that becomes a Ligand Unit.
  • conjugation will be via an introduced cysteine residue as well as reduced interchain disulfides and there will be from 1 to 10 or 1 to 12 or 1 to 14 or 1 to 16 Drug-Linker Compound moieties conjugated to a Ligand Unit. In some embodiments, conjugation will be via an introduced cysteine residue and there will be 2 or 4 Drug-Linker Compound molecules conjugated to a Ligand Unit.
  • Ligand Unit L [0427] In some embodiments of the invention, a Ligand Unit is present.
  • the Ligand Unit (L-) is a targeting agent that specifically binds to a target moiety. In one group of embodiments, the Ligand Unit specifically and selectively binds to a cell component (a Cell Binding Agent) or to another target molecule of interest.
  • the Ligand Unit acts to target and present the Drug Unit (such as one of Formula (I) or any subformula thereof) to the particular target cell population with which the Ligand Unit interacts due to the presence of its targeted component or molecule and allows for subsequent release of free drug within (i.e., intracellularly) or within the vicinity of the target cells (i.e., extracellularly).
  • Ligand Units, L include, but are not limited to, proteins, polypeptides and peptides.
  • Suitable Ligand Units include, for example, antibodies, e.g., full-length antibodies and antigen binding fragments thereof, interferons, lymphokines, hormones, growth factors and colony-stimulating factors, vitamins, nutrient-transport molecules (such as, but not limited to, transferrin), or any other cell binding molecule or substance.
  • the Ligand Unit (L) is from an antibody or a non-antibody protein targeting agent.
  • a Ligand Unit is bonded to Q (a Linker Unit) which comprises a Glucuronide Releasable Linker.
  • linking components are present in the conjugates described herein to serve the purpose of providing additional space between the Drug Unit compound and the Ligand Unit (e.g., a Stretcher Unit and optionally a Connector Unit, A), or providing attributes to the composition to increases solubility (e.g., a Partitioning Agent, S * ).
  • the Ligand Unit is bonded to Z of the Linker Unit via a heteroatom of the Ligand Unit.
  • Heteroatoms that may be present on a Ligand Unit for that bonding include sulfur (in one embodiment, from a sulfhydryl group of a targeting ligand), oxygen (in one embodiment, from a carboxyl or hydroxyl group of a targeting ligand) and nitrogen, optionally substituted (in one embodiment, from a primary or secondary amine functional group of a targeting ligand or in another embodiment from an optionally substituted amide nitrogen).
  • Those heteroatoms are present on the targeting ligand in the ligand’s natural state, for example in a naturally occurring antibody, or are introduced into the targeting ligand via chemical modification or biological engineering.
  • the Ligand Unit is an antibody.
  • Useful polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of immunized animals.
  • Useful monoclonal antibodies are homogeneous populations of antibodies to a particular antigenic determinant (e.g., a cancer or immune cell antigen, a protein, a peptide, a carbohydrate, a chemical, nucleic acid, or fragments thereof).
  • a monoclonal antibody (mAb) to an antigen-of-interest can be prepared by using any technique known in the art which provides for the production of antibody molecules by continuous cell lines in culture.
  • Useful monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, or chimeric human-mouse (or other species) monoclonal antibodies.
  • the antibodies include full-length antibodies and antigen binding fragments thereof.
  • Human monoclonal antibodies may be made by any of numerous techniques known in the art (e.g., Teng et al., 1983, Proc. Natl. Acad. Sci. USA. 80:7308- 7312; Kozbor et al., 1983, Immunology Today 4:72-79; and Olsson et al., 1982, Meth. Enzymol. 92:3-16).
  • an antibody includes a functionally active fragment, derivative or analog of an antibody that binds specifically to target cells (e.g., cancer cell antigens) or other antibodies bound to cancer cells or matrix.
  • target cells e.g., cancer cell antigens
  • “functionally active” means that the fragment, derivative or analog is able to bind specifically to target cells.
  • synthetic peptides containing the CDR sequences are typically used in binding assays with the antigen by any binding assay method known in the art (e.g., the Biacore assay) (See, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md; Kabat E et al., 1980, J. Immunology 125(3):961-969).
  • recombinant antibodies such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which are typically obtained using standard recombinant DNA techniques, are useful antibodies.
  • a chimeric antibody is a molecule in which different portions are derived from different animal species, such as for example, those having a variable region derived from a murine monoclonal and a constant region derived from a human immunoglobulin. See, e.g., U.S. Patent No. 4,816,567; and U.S. Patent No. 4,816,397, which are incorporated herein by reference in their entireties.
  • Humanized antibodies are antibody molecules from non-human species having one or more CDRs from the non-human species and a framework region from a human immunoglobulin molecule. See, e.g., U.S. Patent No. 5,585,089, which is incorporated herein by reference in its entirety.
  • Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in International Publication No. WO 87/02671; European Patent Publication No. 0184187; European Patent Publication No. 0171496; European Patent Publication No. 0173494; International Publication No. WO 86/01533; U.S. Patent No. 4,816,567; European Patent Publication No. 012023; Berter et al., 1988, Science 240:1041-1043; Liu et al., 1987, Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al., 1987, J. Immunol.
  • an antibody is a completely human antibody.
  • an antibody is produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chain genes, but which are capable of expressing human heavy and light chain genes.
  • an antibody is an intact or fully-reduced antibody.
  • the term ‘fully-reduced’ is meant to refer to an antibody in which all four inter-chain disulfide linkages have been reduced to provide eight thiols that can be attached to a linker (L).
  • Attachment to an antibody can be via thioether linkages from native and/or engineered cysteine residues, or from an amino acid residue engineered to participate in a cycloaddition reaction (such as a click reaction) with the corresponding linker intermediate. See, e.g., Maerle, et al., PLOS One 2019: 14(1); e0209860.
  • an antibody is an intact or fully-reduced antibody, or is an antibody bearing engineered an cysteine group that is modified with a functional group that can participate in, for example, click chemistry or other cycloaddition reactions for attachment of other components of the ADC as described herein (e.g., Diels-Alder reactions or other [3+2] or [4+2] cycloadditions).
  • a functional group that can participate in, for example, click chemistry or other cycloaddition reactions for attachment of other components of the ADC as described herein (e.g., Diels-Alder reactions or other [3+2] or [4+2] cycloadditions).
  • Antibodies that bind specifically to a cancer or immune cell antigen are available commercially or produced by any method known to one of skill in the art such as, e.g., chemical synthesis or recombinant expression techniques.
  • the nucleotide sequences encoding antibodies that bind specifically to a cancer or immune cell antigen are obtainable, e.g., from the GenBank database or similar database, literature publications, or by routine cloning and sequencing.
  • the antibody can be used for the treatment of a cancer (e.g., an antibody approved by the FDA and/or EMA).
  • a cancer e.g., an antibody approved by the FDA and/or EMA.
  • Antibodies that bind specifically to a cancer or immune cell antigen are available commercially or produced by any method known to one of skill in the art such as, e.g., recombinant expression techniques.
  • the nucleotide sequences encoding antibodies that bind specifically to a cancer or immune cell antigen are obtainable, e.g., from the GenBank database or similar database, literature publications, or by routine cloning and sequencing.
  • the antibody has a mutation or post-translational modification which affects non-Fab mediated uptake.
  • an antibody can be configured to bind to a surface antigen of a cell.
  • the antibody, or a complex comprising the antibody can be configured to internalize within a cell upon binding to the surface antigen.
  • the antibody or an ADC comprising the antibody can be configured to endocytose upon binding to a surface antigen of a cell.
  • the antibody (or an ADC comprising the antibody) is configured to internalize within a cancer cell.
  • the antibody (or an ADC comprising the antibody) is configured to internalize within an immune cell.
  • the immune cell is a tumor associated macrophage.
  • the surface antigen is a receptor or a receptor complex (e.g., expressed on lymphocytes).
  • the receptor or receptor complex comprises an immunoglobulin gene superfamily member, a TNF receptor superfamily member, an integrin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement control protein or other immune cell expressed surface receptor.
  • an antibody is configured to bind specifically to a cancer cell antigen.
  • an antibody is configured to bind specifically to an immune cell antigen.
  • the immune cell antigen is a tumor associated macrophage antigen.
  • an antibody is configured to bind specifically to EphA2.
  • the antibody component in an ADC is an antibody in residue form such that “Ab” in the ADC structures described herein incorporates the structure of the antibody.
  • Non-limiting examples of antibodies that can be used for treatment of cancer and antibodies that bind specifically to tumor associated antigens are disclosed in Franke, A. E., Sievers, E. L., and Scheinberg, D. A., “Cell surface receptor-targeted therapy of acute myeloid leukemia: a review” Cancer Biother Radiopharm. 2000,15, 459-76; Murray, J. L., “Monoclonal antibody treatment of solid tumors: a coming of age” Semin Oncol.
  • Non-limiting examples of antigens which antibodies of the present disclosure may target include ADAM12 (e.g., Catalog #14139-1-AP); ADAM9 (e.g., IMGC936); AFP (e.g., ThermoFisher Catalog #PA5-25959); AGR2 (e.g., ThermoFisher Catalog #PA5-34517); AKAP-4 (e.g., Catalog #PA5-52230); ALK (e.g., DLX521); ALPP (e.g., Catalog #MA5- 15652); ALPPL2 (e.g., Catalog #PA5-22336); AMHR2 (e.g., ThermoFisher Catalog #PA5- 13902); androgen receptor (e.g.
  • CAMPATH-1 e.g., alemtuzumab; ALLO-647; ANT1034
  • carcinoembryonic antigen e.g., arcitumomab; cergutuzumab; amunaleukin; labetuzumab
  • CCNB1 CD112
  • CD115 e.g., axatilimab; cabiralizumab; emactuzumab
  • CD123 e.g., BAY-943; CSL360
  • CD137 e.g., ADG106; CTX-471
  • CD138 e.g., CD142
  • CD166 e.g., gavilimomab; metuzumab
  • CD155 e.g., U.S. Publication No. 2018/0251548
  • CD19 e.g., ALLO-501
  • CD20 e.g., divozilimab; ibritumomab tiuxetan
  • CD24 see, e.g., U.S. Patent No.
  • CD244 e.g., R&D AF1039
  • CD247 e.g., AFM15
  • CD27 e.g., varlilumab
  • CD274 e.g., adebrelimab; atezolizumab; garivulimab
  • CD3 e.g., otelixizumab; visilizumab
  • CD30 e.g., iratumumab
  • CD33 e.g., lintuzumab; BI 836858; AMG 673
  • CD288; CD352 e.g., SGN-CD352A
  • CD37 e.g., lilotomab; GEN3009
  • CD38 e.g., felzartamab; AMG 424
  • CD3D CD3E
  • CD3G CD45 (e.g., apamistamab
  • CD79b CD96
  • CD97 CD-262 (e.g., tigatuzumab); CDCP1 (e.g., RG7287); CDH17 (see, e.g., International Publication No.
  • WO 2018115231 CDH3 (e.g., PCA062); CDH6 (e.g., HKT288); CEACAM1; CEACAM5; CEACAM6; CLDN1 (e.g., INSERM anti-Claudin-1); CLDN16; CLDN18.1 (e.g., zolbetuximab); CLDN18.2 (e.g., zolbetuximab); CLDN19; CLDN2 (see, e.g., International Publication No. WO 2018123949); CLEC12A (e.g., tepoditamab); CS1; CLPTM1L; CSPG4 (e.g., U.S. Patent No.
  • CXCR4 e.g., ulocuplumab
  • CYP1B1 e.g., c-Met
  • DCLK1 see, e.g., International Publication No. WO 2018222675
  • DDR1; de2-7 EGFR e.g., MAb 806); DLL-3; DPEP1; DPEP3; DPP4; DR4 (e.g., mapatumumab); DSG2 (see, e.g., U.S. Patent No.
  • EGF EGF
  • EGFR endosialin
  • ENPP1 EPCAM
  • EPHA receptors EPHA2
  • ERBB2 e.g., trastuzumab
  • ERBB3 e.g., ERVMER34_1
  • ETV6-AML e.g., Catalog #PA5-81865
  • FAS FasL
  • Fas-related antigen 1 FBP
  • FGFR1 e.g., RG7992
  • FGFR2 e.g., aprutumab
  • FGFR3 e.g., vofatamab
  • FGFR4 e.g., MM-161
  • FLT3 e.g., 4G8SDIEM
  • FN FN1
  • FOLR1 e.g., farletuzumab
  • FRa FSHR
  • FucGM1 e.g., BMS-AML
  • PR1; PROM1 e.g., Catalog #14- 1331-82
  • PSA e.g., ThermoFisher Catalog #PA1-38514; Daniels-Wells et al. BMC Cancer 2013; 13:195
  • PSCA e.g., AGS-1C4D4
  • PSMA e.g., BAY 2315497
  • PTK7 e.g., cofetuzumab
  • PVRIG Ras mutant (e.g., Shin et al. Sci Adv.
  • RET e.g., WO2020210551
  • RGS5 e.g., TF-TA503075
  • RhoC e.g., ThermoFisher Catalog PA5-77866
  • ROR1 e.g., cirmtuzumab
  • ROR2 e.g., BA3021
  • ROS1 e.g., WO 2019107671
  • Sarcoma translocation breakpoints SART3 (e.g., TF 18025-1-AP); Sialyl- Thomsen-nouveau-antigen (e.g., Eavarone et al. PLoS One.
  • SIRPa e.g., Catalog #17-1729-42
  • SIRPg e.g., PA5-104381
  • SIT1 e.g., PA5-53825
  • SLAMF7 e.g., elotuzumab
  • SLC10A2 e.g., ThermoFisher Catalog #PA5-18990
  • SLC12A2 e.g., ThermoFisher Catalog #13884-1-AP
  • SLC17A2 e.g., ThermoFisher Catalog #PA5- 106752
  • SLC38A1 e.g., ThermoFisher Catalog #12039-1-AP
  • SLC39A5 e.g., ThermoFisher Catalog #MA5-27260
  • SLC39A6 e.g.
  • Non-limiting examples of target antigens include Axl (e.g., BA3011; tilvestamab); B7-1 (e.g., galiximab); B7-2 (e.g., Catalog #12-0862-82); B7-DC (e.g., Catalog #PA5- 20344); B7-H3 (e.g., enoblituzumab, omburtamab, MGD009, MGC018, DS-7300); B7-H4 (e.g., Catalog #14-5949-82); B7-H6 (e.g., Catalog #12-6526-42); B7-H7; BAFF-R (e.g., Catalog #14-9117-82); BCMA; C5 complement (e.g., BCD-148; CAN106); CCR4 (e.g., AT008; mogamulizumab-kpkc); CCR8 (e.g., JTX-1811); CD112 (see,
  • CD115 e.g., axatilimab; cabiralizumab; emactuzumab
  • CD123 e.g., BAY-943; CSL360
  • CD137 e.g., ADG106; CTX-471
  • CD155 e.g., U.S. Publication No. 2018/0251548
  • CD163 e.g., TBI 304H
  • CD19 e.g., ALLO-501
  • CD2 e.g., BTI-322; siplizumab
  • CD20 e.g., divozilimab; ibritumomab
  • CD24 see, e.g., U.S. Patent No.
  • CD244 e.g., R&D AF1039
  • CD247 e.g., AFM15
  • CD25 e.g., basiliximab
  • CD27 e.g., varlilumab
  • CD274 e.g., adebrelimab; atezolizumab; garivulimab
  • CD278 e.g., feladilimab; vopratelimab
  • CD28 e.g., REGN5668
  • CD3 e.g., otelixizumab; visilizumab
  • CD30 e.g., iratumumab
  • CD30L see, e.g., U.S. Patent No.
  • CD32 e.g., mAb 2B6
  • CD33 e.g., lintuzumab; BI 836858; AMG 673
  • CD352 e.g., SGN- CD352A
  • CD37 e.g., lilotomab; GEN3009
  • CD38 e.g., felzartamab; AMG 424
  • CD3D e.g., foralumab; teplizumab
  • CD3G e.g., dacetuzumab; lucatumumab
  • CD44 e.g., RG7356
  • CD45 e.g., apamistamab
  • CD47 e.g., letaplimab; magrolimab
  • CD48 e.g., SGN-CD48A
  • CD5 e.g., MAT 304; zolimomab aritox
  • CD51 e.g.
  • CD83 e.g., CBT004
  • CD97 CD262 (e.g., tigatuzumab); CLEC12A (e.g., tepoditamab); CTLA4 (e.g., ipilimumab); CXCR4 (e.g., ulocuplumab); DCIR; DCSIGN (see, e.g., International Publication No. WO 2018134389); Dectin1 (see, e.g., U.S. Patent No.
  • Dectin2 e.g., ThermoFisher Catalog #MA5-16250
  • DR4 e.g., mapatumumab
  • endosialin e.g., ontuxizumab
  • FasL FLT3 (e.g., 4G8SDIEM); GITR (e.g., ragifilimab); HAVCR2; HER2; HER3; HLA-DR; HLA-E; HLA-F; HLA-G (e.g., TTX-080); ICAM1; IDO1; IFNAR1 (e.g., faralimomab); IFNAR2; IGF-1R; IL1RAP (e.g., nidanilimab); IL-21R (e.g., PF-05230900); IL-5R (e.g., benralizumab); Integrin ⁇ v ⁇ 6; LAG-3 (e.g.
  • SIRPa e.g., Catalog #17-1729-42
  • SIRPg e.g., PA5-104381
  • SIT1 e.g., PA5-53825
  • SLAMF7 e.g., elotuzumab
  • SLTRK6 e.g., STEAP1
  • TIGIT e.g., etigilimab
  • TLR2/4/1 e.g., tomaralimab
  • Trem2 e.g., PY314
  • TROP2 Tyrol
  • ULBP1/2/3/4/5/6 e.g., PA5-82302
  • uPAR e.g., ATN-658
  • VSIR e.g., ThermoFisher Catalog #PA5-52493
  • ZIP6 Anti- Integrity
  • an antibody target is selected from the group consisting of ADAM9, ASCT2, Axl, B7-H3, B7H4, BCMA, BCMA, C4.4a, CanAg, CD123, CD138, CD142, CD166, CD19, CD20, CD228, CD25, CD30, CD33, CD352, CD38, CD48, CD56, CD59, CD70, CD74, CD79b, CDCP1, CEACAM5, Claudin-18.2, c-Met, gpNMB, CS1, DLL-3, DPEP-3, EGFR, EpCAM, EphA2, FGFR2, FRa, GCC, gpA33, GPC3, Integrin ⁇ v ⁇ 6 , h2A2, H2G12/STn, HER2, HER3, ZIP6, IGF-1R, IL1Rap, ITGav/CD51, Mesothelin, MICA, MUC-1, Muc16, Na
  • an antibody of the present disclosure comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, and wherein: the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 44 and the second sequence is SEQ ID NO: 45; the first sequence is SEQ ID NO: 55 and the second sequence is SEQ ID NO: 56; the first sequence is SEQ ID NO: 69 and the second sequence is SEQ ID NO: 70; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121 and the second
  • an antibody of the present disclosure targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, and TIGIT.
  • the antibody comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121 and the second sequence is SEQ ID NO: 122; the first sequence is SEQ ID NO: 129 and the second sequence is SEQ ID NO:
  • an antibody of the present disclosure comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO: 113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121 and the second sequence is SEQ ID NO: 122; the first sequence is SEQ ID NO: 129 and the second sequence is SEQ ID NO: 130; the first sequence is SEQ ID NO: 137 and the second sequence is SEQ ID NO: 138; the first sequence is SEQ ID NO: 19 and the second sequence is SEQ
  • the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20.
  • the heavy chain variable region has at least 85% sequence identity to the first sequence and the light chain variable region has at least 85% sequence identity to the second sequence.
  • the heavy chain variable region has at least 90% sequence identity to the first sequence and the light chain variable region has at least 90% sequence identity to the second sequence.
  • the heavy chain variable region has at least 95% sequence identity to the first sequence and the light chain variable region has at least 95% sequence identity to the second sequence.
  • the heavy chain variable region has at least 98% sequence identity to the first sequence and the light chain variable region has at least 98% sequence identity to the second sequence.
  • an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10;
  • an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 85 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 1 and
  • an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 85 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 1 and
  • an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; or the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10.
  • an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 3 or SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5.
  • the heavy chain has at least 85% sequence identity to the first sequence and the light chain has at least 85% sequence identity to the second sequence.
  • the heavy chain has at least 90% sequence identity to the first sequence and the light chain has at least 90% sequence identity to the second sequence.
  • the heavy chain has at least 95% sequence identity to the first sequence and the light chain has at least 95% sequence identity to the second sequence.
  • the heavy chain has at least 98% sequence identity to the first sequence and the light chain has at least 98% sequence identity to the second sequence. In some cases, the heavy chain has at least 99% sequence identity to the first sequence and the light chain has at least 99% sequence identity to the second sequence. In some cases, the heavy chain comprises the first sequence and the light chain comprises the second sequence.
  • an antibody of the present disclosure comprises CDR-H1, CDR- H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising at least 80% sequence identity to: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively (i.e., CDR-H1 has at least 80% sequence identity to SEQ ID NO: 13, CDR-H2 has at least 80% sequence identity to SEQ ID NO: 14, CDR-H3 has at least 80% sequence identity to SEQ ID NO: 15, CDR-L1 has at least 80% sequence identity to SEQ ID NO: 16, CDR-L2 has at least 80% sequence identity to SEQ ID NO: 17, and CDR-L3 has at least 80% sequence identity to SEQ ID NO: 18); SEQ ID NO: 21, 22, 23, 24, 25, and 26, respectively; SEQ ID NO: 38, 39, 40, 41, 42, and 43, respectively; SEQ ID NO: 49, 50, 51, 52, 53,
  • an antibody of the present disclosure targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, and TIGIT.
  • an antibody of the present disclosure comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 comprising at least 80% sequence identity to: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NO: 77, 78, 79, 80, 81, and 82, , respectively; SEQ ID NO: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NO: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NO: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NO: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NO: 123, 124, 125, 126, 127,
  • the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise at least 85% sequence identity to the respective 6 indicated sequences. In some cases, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprise at least 90% sequence identity to the respective 6 indicated sequences. In some cases, the CDR- H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprise at least 95% sequence identity to the respective 6 indicated sequences.
  • the CDR-H1, CDR- H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprise at most one mutation relative to the respective 6 indicated sequences.
  • an antibody provided herein binds to PDL1.
  • PDL1 is expressed in a broad range of cancers, as well as certain immune cells, and often serves as a primary mechanism for immune suppression in tumor microenvironments.
  • the PDL1 agonism of PD- 1 can act as an immune checkpoint, diminishing lymphocyte tumor infiltration, and T-cell receptor mediated proliferation and signaling.
  • an anti-PDL1 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18 respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively.
  • the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 1-4 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5.
  • the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5.
  • the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5.
  • the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 3 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5.
  • the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 4 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5.
  • the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 6- 9 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 6 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 8 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 9 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 20.
  • an antibody provided herein binds to EphA2.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequences of SEQ ID NOs: 21, 22, 23, 24, 25, and 26, respectively.
  • the anti-EphA2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 28.
  • the anti-EphA2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of the amino acid sequence of SEQ ID NO: 31.
  • the anti-EphA2 antibody comprises a heavy chain comprising the amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 34.
  • the anti-EphA2 antibody comprises a heavy chain that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 35 or SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 37.
  • the antibody is h1C1 or 1C1.
  • the anti-EphA2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 28.
  • an antibody provided herein binds to CD30.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively.
  • the anti-CD30 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 46 or 47 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 48.
  • the anti-CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 44 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 45.
  • an antibody provided herein binds to CD228.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively.
  • the anti-CD228 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 56.
  • the anti-CD228 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either of SEQ ID NO: 57 or 58 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 59.
  • the anti-CD228 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either of SEQ ID NO: 60 or 61 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 62.
  • an antibody provided herein binds to avB6.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively.
  • the anti-H2A2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70.
  • the anti-H2A2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 71 or 72 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73.
  • the anti-H2A2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 74 or 75 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76.
  • the anti-avB6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70.
  • the anti-avB6 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 71 or 72 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73.
  • the anti-avB6 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 74 or 75 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76.
  • an antibody provided herein binds to B7H4.
  • the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 77-82, SEQ ID NOs: 91-96, SEQ ID NOs: 99-104, SEQ ID NOs: 107-112, SEQ ID NOs: 115-120, SEQ ID NOs: 123-128, SEQ ID NOs: 131- 136, SEQ ID NOs: 139-144, SEQ ID NOs: 147-152, SEQ ID NOs: 155-160, SEQ ID NOs: 163-168, SEQ ID NOs: 171-176, SEQ ID NOs: 179-184, SEQ ID NOs: 187-192
  • the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3, respectively) each comprising at most one mutation relative to an amino acid sequence from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 77-82, SEQ ID NOs: 91-96, SEQ ID NOs: 99-104, SEQ ID NOs: 107-112, SEQ ID NOs: 115-120, SEQ ID NOs: 123-128, SEQ ID NOs: 131-136, SEQ ID NOs: 139-144, SEQ ID NOs: 147-152, SEQ ID NOs: 155-160, SEQ ID NOs: 163-168, SEQ ID NOs: 171-176, SEQ ID NOs: 179-184, SEQ ID NOs: 187-192, SEQ ID NOs: 195-200, SEQ ID NOs: 203- 208, SEQ ID NOs:
  • the anti-B7H4 antibody comprises a heavy chain and a light chain comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 85 and 87, SEQ ID NO: 86 and 87, SEQ ID NO: 88 and 90, SEQ ID NO: 89 and 90, SEQ ID NO: 251 and 252, , SEQ ID NO: 253 and 254, SEQ ID NO: 255 and 256, SEQ ID NO: 257 and 258, SEQ ID NO: 259 and 260, SEQ ID NO: 261 and 262, SEQ ID NO: 263 and 264, SEQ ID NO: 265 and 266, SEQ ID NO: 267 and 268, SEQ ID NO: 269 and 270, SEQ ID NO: 271 and 272, SEQ ID NO: 273 and 274, SEQ ID NO: 275 and 276, SEQ ID NO: 277
  • the anti-B7H4 antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 83 and 84, SEQ ID NO: 97 and 98, SEQ ID NO: 105 and 106, SEQ ID NO: 113 and 114, SEQ ID NO: 121 and 122, SEQ ID NO: 129 and 130, SEQ ID NO: 137 and 138, SEQ ID NO: 153 and 154, SEQ ID NO: 161 and 162, SEQ ID NO: 169 and 170, SEQ ID NO: 177 and 178, SEQ ID NO: 185 and 186, SEQ ID NO: 193 and 194, SEQ ID NO: 201 and 202, SEQ ID NO: 209 and 210, SEQ ID NO: 217 and 218, SEQ ID NO: 225
  • an antibody provided herein binds to CD70.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively.
  • the anti-CD70 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 297 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 298.
  • the anti- CD70 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 299 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 300.
  • an antibody provided herein binds to TROP2.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively.
  • an antibody provided herein binds to TROP2.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 309, 310, 311, 312, 313, and 314 respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 309, 310, 311, 312, 313, and 314, respectively.
  • the anti-TROP2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 307 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 308.
  • the anti-TROP2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 315 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 316.
  • an antibody provided herein binds to MICA.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively.
  • the anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 323 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 324.
  • the anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 331 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 332.
  • the anti- MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 340 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 340.
  • the anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 347 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 348.
  • an antibody provided herein binds to CD51.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively.
  • an antibody provided herein binds to CD51.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 357, 358, 359, 360, 361, and 362, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 357, 358, 359, 360, 361, and 362, respectively.
  • the anti-CD51 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 355 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 356.
  • the anti-CD51 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 363 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 364.
  • an antibody provided herein binds to gpA33.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 365, 366, 367, 368, 369, and 370, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 365, 366, 367, 368, 369, and 370, respectively.
  • the anti-gpA33 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 371 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 372.
  • an antibody provided herein binds to IL1Rap.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively.
  • the anti-IL1Rap antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 379 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 380.
  • an antibody provided herein binds to EpCAM.
  • the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 381-386, SEQ ID NOs: 389-394, SEQ ID NOs: 397- 402, SEQ ID NOs: 405-410, SEQ ID NOs: 413-418, or SEQ ID NOs: 421-426.
  • the anti-EpCAM antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 387 and 388, SEQ ID NO: 395 and 396, SEQ ID NO: 403 and 404, SEQ ID NO: 411 and 412, SEQ ID NO: 419 and 420, or SEQ ID NO: 427 and 428, respectively.
  • an antibody provided herein binds to CD352.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively.
  • the anti-CD352 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 435 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 436.
  • an antibody provided herein binds to CS1.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively.
  • the anti-CS1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 443 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 444.
  • an antibody provided herein binds to CD38.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 445, 446, 447, 448, 449, and 450, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 445, 446, 447, 448, 449, and 450, respectively.
  • the anti-CD38 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 451 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 452.
  • an antibody provided herein binds to CD25.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively.
  • the anti-CD25 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 459 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 460.
  • an antibody provided herein binds to ADAM9.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively.
  • the antibody comprises CDR- H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 469, 470, 471, 472, 473, and 474, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 469, 470, 471, 472, 473, and 474, respectively.
  • the anti-ADAM9 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 467 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 468.
  • the anti-ADAM9 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 475 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 476.
  • an antibody provided herein binds to CD59.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 477, 478, 479, 480, 481, and 482, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 477, 478, 479, 480, 481, and 482, respectively.
  • the anti-CD59 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 483 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 484.
  • an antibody provided herein binds to CD19.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 485, 486, 487, 488, 489, and 490, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 485, 486, 487, 488, 489, and 490, respectively.
  • the anti-CD19 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 491 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 492.
  • the anti- CD19 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 493 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 494.
  • an antibody provided herein binds to CD138.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 495, 496, 497, 498, 499, and 500, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 495, 496, 497, 498, 499, and 500, respectively.
  • the anti-CD138 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 501 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 502.
  • an antibody provided herein binds to CD166.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 503, 504, 505, 506, 507, and 508, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 503, 504, 505, 506, 507, and 508, respectively.
  • the anti-CD166 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 509 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 510.
  • an antibody provided herein binds to CD56.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively.
  • the anti-CD56 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 517 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 518.
  • an antibody provided herein binds to CD74.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 519, 520, 521, 522, 523, and 524, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 519, 520, 521, 522, 523, and 524, respectively.
  • the anti-CD74 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 525 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 526.
  • an antibody provided herein binds to CEACAM5.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 527, 528, 529, 530, 531, and 532, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 527, 528, 529, 530, 531, and 532, respectively.
  • the anti-CEACAM5 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 533 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 534.
  • an antibody provided herein binds to CanAg.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively.
  • the anti-CanAg antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 541 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 542.
  • an antibody provided herein binds to DLL-3.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 543, 544, 545, 546, 547, and 548, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 543, 544, 545, 546, 547, and 548, respectively.
  • the anti-DLL-3 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 549 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 550.
  • an antibody provided herein binds to DPEP-3.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 551, 552, 553, 554, 555, and 556, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 551, 552, 553, 554, 555, and 556, respectively.
  • the anti-DPEP-3 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 557 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 558.
  • an antibody provided herein binds to EGFR.
  • the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 559-564, SEQ ID NOs: 567-572, SEQ ID NOs: 575- 580, and SEQ ID NOs: 895-900.
  • the anti-EGFR antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 565 and 566, SEQ ID NO: 573 and 574, SEQ ID NO: 581 and 582, or SEQ ID NO: 901 and 902, respectively.
  • an antibody provided herein binds to FRa.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 583, 584, 585, 586, 587, and 588, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 583, 584, 585, 586, 587, and 588, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 591, 592, 593, 594, 595, and 596, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 591, 592, 593, 594, 595, and 596, respectively.
  • the anti-FRa antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 589 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 590.
  • the anti-FRa antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 597 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 598.
  • an antibody provided herein binds to MUC-1.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 599, 600, 601, 602, 603, and 604, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 599, 600, 601, 602, 603, and 604, respectively.
  • the anti-MUC-1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 605 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 606.
  • an antibody provided herein binds to Mesothelin.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 607, 608, 609, 610, 611, and 612, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 607, 608, 609, 610, 611, and 612, respectively.
  • the anti-Mesothelin antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 613 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 614.
  • an antibody provided herein binds to ROR-1.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 615, 616, 617, 618, 619, and 620, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 615, 616, 617, 618, 619, and 620, respectively.
  • the anti-ROR-1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 621 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 622.
  • an antibody provided herein binds to B7H3.
  • the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 623-628, SEQ ID NOs: 631-636, SEQ ID NOs: 639- 644, SEQ ID NOs: 647-652, SEQ ID NOs: 655-660, SEQ ID NOs: 663-668, SEQ ID NOs: 671-676, SEQ ID NOs: 679-684, SEQ ID NOs: 687-692, SEQ ID NOs: 695-700, and SEQ ID NOs: 705-710.
  • the anti-B7H3 antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 629 and 630, SEQ ID NOs: 637 and 638, SEQ ID NOs: 645 and 646, SEQ ID NOs: 653 and 654, SEQ ID NOs: 661 and 662, SEQ ID NOs: 669 and 670, SEQ ID NOs: 677 and 678, SEQ ID NOs: 685 and 686, SEQ ID NOs: 693 and 694, SEQ ID NOs: 701 and 702, SEQ ID NOs: 703 and 704, SEQ ID NOs: 711 and 712, SEQ ID NOs: 713 and 714, and SEQ ID NOs: 715 and 716, respectively.
  • an antibody provided herein binds to HER3.
  • the anti-HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 717 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 718.
  • an antibody provided herein binds to HER3.
  • the anti-HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 719 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 720.
  • an antibody provided herein binds to HER3.
  • the anti-HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 721 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 722.
  • an antibody provided herein binds to HER3.
  • the anti-HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 723 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 724.
  • an antibody provided herein binds to PTK7.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 725, 726, 727, 728, 729, and 730, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 725, 726, 727, 728, 729, and 730, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 733, 734, 735, 736, 737, and 738, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 733, 734, 735, 736, 737, and 738, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 741, 742, 743, 744, 745, and 746, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 741, 742, 743, 744, 745, and 746, respectively.
  • the anti-PTK7 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 731 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 732.
  • the anti-PTK7 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 739 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 740.
  • the anti-PTK7 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 747 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 748.
  • an antibody provided herein binds to ZIP6.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 749, 750, 751, 752, 753, and 754, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 749, 750, 751, 752, 753, and 754, respectively.
  • the anti-ZIP6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 755 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 756.
  • the anti-ZIP6 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 757 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 758.
  • an antibody provided herein binds to Integrin ⁇ v ⁇ 6.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 759, 760, 761, 762, 763, and 764, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 759, 760, 761, 762, 763, and 764, respectively.
  • the anti- Integrin ⁇ v ⁇ 6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 765 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 766.
  • an antibody provided herein binds to CD48.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 767, 768, 769, 770, 771, and 772, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 767, 768, 769, 770, 771, and 772, respectively.
  • the anti-CD48 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 773 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 774.
  • an antibody provided herein binds to IGF-1R.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 775, 776, 777, 778, 779, and 780, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 775, 776, 777, 778, 779, and 780, respectively.
  • the anti-IGF-1R antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 781 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 782.
  • an antibody provided herein binds to Claudin-18.2.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 783, 784, 785, 786, 787, and 788, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 783, 784, 785, 786, 787, and 788, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 791, 792, 793, 794, 795, and 796, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 791, 792, 793, 794, 795, and 796, respectively.
  • the anti-Claudin-18.2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 789 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 790.
  • the anti-Claudin-18.2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 797 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 798.
  • an antibody provided herein binds to Nectin-4.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 799, 800, 801, 802, 803, and 804, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 799, 800, 801, 802, 803, and 804, respectively.
  • the anti-Nectin-4 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 805 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 806.
  • an antibody provided herein binds to SLTRK6.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 807, 808, 809, 810, 811, and 812, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 807, 808, 809, 810, 811, and 812, respectively.
  • the anti-SLTRK6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 813 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 814.
  • an antibody provided herein binds to CD142.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 815, 816, 817, 818, 819, and 820, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 815, 816, 817, 818, 819, and 820, respectively.
  • the anti-CD142 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 821 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 822.
  • an antibody provided herein binds to Sialyl-Thomsen-nouveau antigen (STn).
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 823, 824, 825, 826, 827, and 828, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 823, 824, 825, 826, 827, and 828, respectively.
  • the anti-STn antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 829 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 830.
  • an antibody provided herein binds to CD20.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 831, 832, 833, 834, 835, and 836, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 831, 832, 833, 834, 835, and 836, respectively.
  • the anti-CD20 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 837 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 838.
  • an antibody provided herein binds to HER2.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 839, 840, 841, 842, 843, and 844, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 839, 840, 841, 842, 843, and 844, respectively.
  • the anti-HER2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 845 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 846.
  • an antibody provided herein binds to CD79b.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 847, 848, 849, 850, 851, and 852, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 847, 848, 849, 850, 851, and 852, respectively.
  • the anti-CD79b antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 853 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 854.
  • an antibody provided herein binds to NaPi2B.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 855, 856, 857, 858, 859, and 860, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 855, 856, 857, 858, 859, and 860, respectively.
  • the anti-NaPi2B antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 861 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 862.
  • an antibody provided herein binds to Muc16.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 863, 864, 865, 866, 867, and 868, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 863, 864, 865, 866, 867, and 868, respectively.
  • the anti-Muc16 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 869 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 870.
  • an antibody provided herein binds to STEAP1.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 871, 872, 873, 874, 875, and 876, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 871, 872, 873, 874, 875, and 876, respectively.
  • the anti-STEAP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 877 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 878.
  • an antibody provided herein binds to BCMA.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 879, 880, 881, 882, 883, and 884, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 879, 880, 881, 882, 883, and 884, respectively.
  • the anti-BCMA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 885 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 886.
  • an antibody provided herein binds to c-Met.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 887, 888, 889, 890, 891, and 892, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 887, 888, 889, 890, 891, and 892, respectively.
  • the anti-c-Met antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 893 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 893.
  • an antibody provided herein binds to SLAMF7.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 903, 904, 905, 906, 907, and 908, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 903, 904, 905, 906, 907, and 908, respectively.
  • the anti-SLAMF7 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 909 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 910.
  • an antibody provided herein binds to C4.4a.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 911, 912, 913, 914, 915, and 916, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 911, 912, 913, 914, 915, and 916, respectively.
  • the anti-C4.4a antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 917 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 918.
  • an antibody provided herein binds to GCC.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 919, 920, 921, 922, 923, and 924, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 919, 920, 921, 922, 923, and 924, respectively.
  • the anti-GCC antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 925 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 926.
  • an antibody provided herein binds to Axl.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 927, 928, 929, 930, 931, and 932, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 927, 928, 929, 930, 931, and 932, respectively.
  • the anti-Axl antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 933 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 933.
  • an antibody provided herein binds to transmembrane glycoprotein NMB (gpNMB).
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 935, 936, 937, 938, 939, and 940, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 935, 936, 937, 938, 939, and 940, respectively.
  • the anti-gpNMB antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 941 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 942.
  • the anti-gpNMB antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 943 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 944.
  • an antibody provided herein binds to Prolactin receptor.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 945, 946, 947, 948, 949, and 950, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 945, 946, 947, 948, 949, and 950, respectively.
  • the anti- Prolactin receptor antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 951 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 952.
  • an antibody provided herein binds to FGFR2.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 953, 954, 955, 956, 957, and 958, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 953, 954, 955, 956, 957, and 958, respectively.
  • the anti-FGFR2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 959 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 960.
  • an antibody provided herein binds to CDCP1.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 961, 962, 963, 964, 965, and 966, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 969, 970, 971, 972, 973, and 974, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 961, 962, 963, 964, 965, and 966, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 969, 970, 971, 972, 973, and 974, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 977, 978, 979, 980, 981, and 982, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 977, 978, 979, 980, 981, and 982, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 985, 986, 987, 988, 989, and 990, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 985, 986, 987, 988, 989, and 990, respectively.
  • the anti-CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 967 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 968.
  • the anti-CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 975 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 976.
  • the anti- CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 983 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 984.
  • the anti-CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 991 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 992.
  • an antibody provided herein binds to ASCT2.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 997, 998, 999, 1000, 1001, and 1002, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 997, 998, 999, 1000, 1001, and 1002, respectively.
  • the anti-ASCT2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 993 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 994.
  • the anti-ASCT2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 995 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 996.
  • the anti-ASCT2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1003 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1004.
  • an antibody provided herein binds to CD123.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1005, 1006, 1007, 1008, 1009, and 1010, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1005, 1006, 1007, 1008, 1009, and 1010, respectively.
  • the anti-CD123 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1011 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1012.
  • an antibody provided herein binds to GPC3.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1013, 1014, 1015, 1016, 1017, and 1018 respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1013, 1014, 1015, 1016, 1017, and 1018, respectively.
  • the anti-TIGIT antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1027 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1028.
  • an antibody provided herein binds to TIGIT.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively.
  • the anti-BCMA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1043 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1044.
  • an antibody provided herein binds to CD33.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1029, 1030, 1031, 1032, 1033, and 1034, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1029, 1030, 1031, 1032, 1033, and 1034, respectively.
  • the anti-CD33 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1035 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1036.
  • an antibody provided herein binds to BCMA.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1037, 1038, 1039, 1040, 1041, and 1042, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1037, 1038, 1039, 1040, 1041, and 1042, respectively.
  • the anti-BCMA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1043 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1044.
  • L is a ligand (e.g., an antibody) that targets an antigen selected from the group consisting of ADAM12 (e.g., Catalog #14139-1-AP); ADAM9 (e.g., IMGC936); AFP (e.g., ThermoFisher Catalog #PA5-25959); AGR2 (e.g., ThermoFisher Catalog #PA5-34517); AKAP-4 (e.g., Catalog #PA5-52230); ALK (e.g., DLX521); ALPP (e.g., Catalog #MA5- 15652); ALPPL2 (e.g., Catalog #PA5-22336); AMHR2 (e.g., ThermoFisher Catalog #PA5- 13902); androgen receptor (e.g., ThermoFisher Catalog #MA5-13426);
  • ADAM12 e.g., Catalog #14139-1-AP
  • ADAM9 e.g., IMGC
  • CAMPATH-1 e.g., alemtuzumab; ALLO-647; ANT1034
  • carcinoembryonic antigen e.g., arcitumomab; cergutuzumab; amunaleukin; labetuzumab
  • CCNB1 CD112
  • CD115 e.g., axatilimab; cabiralizumab; emactuzumab
  • CD123 e.g., BAY-943; CSL360
  • CD137 e.g., ADG106; CTX-471
  • CD138 e.g., CD142
  • CD166 e.g., gavilimomab; metuzumab
  • CD155 e.g., U.S. Publication No. 2018/0251548
  • CD19 e.g., ALLO-501
  • CD20 e.g., divozilimab; ibritumomab tiuxetan
  • CD24 see, e.g., U.S. Patent No.
  • CD244 e.g., R&D AF1039
  • CD247 e.g., AFM15
  • CD27 e.g., varlilumab
  • CD274 e.g., adebrelimab; atezolizumab; garivulimab
  • CD3 e.g., otelixizumab; visilizumab
  • CD30 e.g., iratumumab
  • CD33 e.g., lintuzumab; BI 836858; AMG 673
  • CD288; CD352 e.g., SGN-CD352A
  • CD37 e.g., lilotomab; GEN3009
  • CD38 e.g., felzartamab; AMG 424
  • CD3D CD3E
  • CD3G CD45 (e.g., apamistamab
  • CD79b CD96
  • CD97 CD-262 (e.g., tigatuzumab); CDCP1 (e.g., RG7287); CDH17 (see, e.g., International Publication No.
  • WO 2018115231 CDH3 (e.g., PCA062); CDH6 (e.g., HKT288); CEACAM1; CEACAM5; CEACAM6; CLDN1 (e.g., INSERM anti-Claudin-1); CLDN16; CLDN18.1 (e.g., zolbetuximab); CLDN18.2 (e.g., zolbetuximab); CLDN19; CLDN2 (see, e.g., International Publication No. WO 2018123949); CLEC12A (e.g., tepoditamab); CS1; CLPTM1L; CSPG4 (e.g., U.S. Patent No.
  • CXCR4 e.g., ulocuplumab
  • CYP1B1 e.g., c-Met
  • DCLK1 see, e.g., International Publication No. WO 2018222675
  • DDR1; de2-7 EGFR e.g., MAb 806); DLL-3; DPEP1; DPEP3; DPP4; DR4 (e.g., mapatumumab); DSG2 (see, e.g., U.S. Patent No.
  • EGF EGF
  • EGFR endosialin
  • ENPP1 EPCAM
  • EPHA receptors EPHA2
  • ERBB2 e.g., trastuzumab
  • ERBB3 e.g., ERVMER34_1
  • ETV6-AML e.g., Catalog #PA5-81865
  • FAS FasL
  • Fas-related antigen 1 FBP
  • FGFR1 e.g., RG7992
  • FGFR2 e.g., aprutumab
  • FGFR3 e.g., vofatamab
  • FGFR4 e.g., MM-161
  • FLT3 e.g., 4G8SDIEM
  • FN FN1
  • FOLR1 e.g., farletuzumab
  • FRa FSHR
  • FucGM1 e.g., BMS-AML
  • PR1; PROM1 e.g., Catalog #14- 1331-82
  • PSA e.g., ThermoFisher Catalog #PA1-38514; Daniels-Wells et al. BMC Cancer 2013; 13:195
  • PSCA e.g., AGS-1C4D4
  • PSMA e.g., BAY 2315497
  • PTK7 e.g., cofetuzumab
  • PVRIG Ras mutant (e.g., Shin et al. Sci Adv.
  • RET e.g., WO2020210551
  • RGS5 e.g., TF-TA503075
  • RhoC e.g., ThermoFisher Catalog PA5-77866
  • ROR1 e.g., cirmtuzumab
  • ROR2 e.g., BA3021
  • ROS1 e.g., WO 2019107671
  • Sarcoma translocation breakpoints SART3 (e.g., TF 18025-1-AP); Sialyl- Thomsen-nouveau-antigen (e.g., Eavarone et al. PLoS One.
  • SIRPa e.g., Catalog #17-1729-42
  • SIRPg e.g., PA5-104381
  • SIT1 e.g., PA5-53825
  • SLAMF7 e.g., elotuzumab
  • SLC10A2 e.g., ThermoFisher Catalog #PA5-18990
  • SLC12A2 e.g., ThermoFisher Catalog #13884-1-AP
  • SLC17A2 e.g., ThermoFisher Catalog #PA5- 106752
  • SLC38A1 e.g., ThermoFisher Catalog #12039-1-AP
  • SLC39A5 e.g., ThermoFisher Catalog #MA5-27260
  • SLC39A6 e.g.
  • L is a ligand (e.g., an antibody) that targets an antigen selected from the group consisting of Axl (e.g., BA3011; tilvestamab); B7-1 (e.g., galiximab); B7-2 (e.g., Catalog #12-0862-82); B7-DC (e.g., Catalog #PA5- 20344); B7-H3 (e.g., enoblituzumab, omburtamab, MGD009, MGC018, DS-7300); B7-H4 (e.g., Catalog #14-5949-82); B7-H6 (e.g., Catalog #12-6526-42); B7-H7; BAFF-R (e.g., Catalog #14-9117-82); BCMA; C5 complement (e.g., BCD-148; CAN106); CCR4 (e.g., AT008; mogamul
  • Axl e.g., BA3011;
  • CD115 e.g., axatilimab; cabiralizumab; emactuzumab
  • CD123 e.g., BAY-943; CSL360
  • CD137 e.g., ADG106; CTX-471
  • CD155 e.g., U.S. Publication No. 2018/0251548
  • CD163 e.g., TBI 304H
  • CD19 e.g., ALLO-501
  • CD2 e.g., BTI-322; siplizumab
  • CD20 e.g., divozilimab; ibritumomab
  • CD24 see, e.g., U.S. Patent No.
  • CD244 e.g., R&D AF1039
  • CD247 e.g., AFM15
  • CD25 e.g., basiliximab
  • CD27 e.g., varlilumab
  • CD274 e.g., adebrelimab; atezolizumab; garivulimab
  • CD278 e.g., feladilimab; vopratelimab
  • CD28 e.g., REGN5668
  • CD3 e.g., otelixizumab; visilizumab
  • CD30 e.g., iratumumab
  • CD30L see, e.g., U.S. Patent No.
  • CD32 e.g., mAb 2B6
  • CD33 e.g., lintuzumab; BI 836858; AMG 673
  • CD352 e.g., SGN- CD352A
  • CD37 e.g., lilotomab; GEN3009
  • CD38 e.g., felzartamab; AMG 424
  • CD3D e.g., foralumab; teplizumab
  • CD3G e.g., dacetuzumab; lucatumumab
  • CD44 e.g., RG7356
  • CD45 e.g., apamistamab
  • CD47 e.g., letaplimab; magrolimab
  • CD48 e.g., SGN-CD48A
  • CD5 e.g., MAT 304; zolimomab aritox
  • CD51 e.g.
  • CD83 e.g., CBT004
  • CD97 CD262 (e.g., tigatuzumab); CLEC12A (e.g., tepoditamab); CTLA4 (e.g., ipilimumab); CXCR4 (e.g., ulocuplumab); DCIR; DCSIGN (see, e.g., International Publication No. WO 2018134389); Dectin1 (see, e.g., U.S. Patent No.
  • Dectin2 e.g., ThermoFisher Catalog #MA5-16250
  • DR4 e.g., mapatumumab
  • endosialin e.g., ontuxizumab
  • FasL FLT3 (e.g., 4G8SDIEM); GITR (e.g., ragifilimab); HAVCR2; HER2; HER3; HLA-DR; HLA-E; HLA-F; HLA-G (e.g., TTX-080); ICAM1; IDO1; IFNAR1 (e.g., faralimomab); IFNAR2; IGF-1R; IL1RAP (e.g., nidanilimab); IL-21R (e.g., PF-05230900); IL-5R (e.g., benralizumab); Integrin ⁇ v ⁇ 6; LAG-3 (e.g.
  • SIRPa e.g., Catalog #17-1729-42
  • SIRPg e.g., PA5-104381
  • SIT1 e.g., PA5-53825
  • SLAMF7 e.g., elotuzumab
  • SLTRK6 e.g., STEAP1
  • TIGIT e.g., etigilimab
  • TLR2/4/1 e.g., tomaralimab
  • Trem2 e.g., PY314
  • TROP2 Tyrol
  • ULBP1/2/3/4/5/6 e.g., PA5-82302
  • uPAR e.g., ATN-658
  • VSIR e.g., ThermoFisher Catalog #PA5-52493
  • ZIP6 Anti-
  • the L moiety of compound 3.1 is a ligand (e.g., an antibody or fragment thereof) that targets ADAM9, ASCT2, Axl, B7-H3, B7H4, BCMA, BCMA, C4.4a, CanAg, CD123, CD138, CD142, CD166, CD19, CD20, CD228, CD25, CD30, CD33, CD352, CD38, CD48, CD56, CD59, CD70, CD74, CD79b, CDCP1, CEACAM5, Claudin- 18.2, c-Met, gpNMB, CS1, DLL-3, DPEP-3, EGFR, EpCAM, EphA2, FGFR2, FRa, GCC, gpA33, GPC3, Integrin ⁇ v ⁇ 6 , h2A2, H2G12/STn, HER2, HER3, ZIP6, IGF-1R, IL1Rap, ITG
  • the L moiety of compound 3.1 comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, and wherein: the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 44 and the second sequence is SEQ ID NO: 45; the first sequence is SEQ ID NO: 55 and the second sequence is SEQ ID NO: 56; the first sequence is SEQ ID NO: 69 and the second sequence is SEQ ID NO: 70; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121
  • the L moiety of compound 3.1 comprises an antibody that targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, and TIGIT.
  • the antibody comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121 and the second sequence is SEQ ID NO: 122; the first sequence is SEQ ID NO: 129 and the second
  • the L moiety of compound 3.1 comprises an antibody comprising a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO: 113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121 and the second sequence is SEQ ID NO: 122; the first sequence is SEQ ID NO: 129 and the second sequence is SEQ ID NO: 130; the first sequence is SEQ ID NO: 137 and the second sequence is SEQ ID NO: 138; the first sequence is SEQ ID NO: 19 and
  • the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20.
  • the heavy chain variable region of the L moiety of compound 3.1 has at least 85% sequence identity to the first sequence and the light chain variable region has at least 85% sequence identity to the second sequence.
  • the heavy chain variable region has at least 90% sequence identity to the first sequence and the light chain variable region has at least 90% sequence identity to the second sequence.
  • the heavy chain variable region has at least 95% sequence identity to the first sequence and the light chain variable region has at least 95% sequence identity to the second sequence.
  • the heavy chain variable region has at least 98% sequence identity to the first sequence and the light chain variable region has at least 98% sequence identity to the second sequence.
  • the heavy chain variable region has at least 99% sequence identity to the first sequence and the light chain variable region has at least 99% sequence identity to the second sequence. In some cases, the heavy chain variable region comprises the first sequence and the light chain variable region comprises the second sequence.
  • the L moiety of compound 3.1 comprises an antibody comprising a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is S
  • the L moiety of compound 3.1 comprises an antibody comprising a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 85 and the second sequence is SEQ ID NO:
  • the L moiety of compound 3.1 comprises an antibody comprising a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 85 and the second sequence is SEQ ID NO:
  • the L moiety of compound 3.1 comprises an antibody comprising a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; or the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10.
  • the L moiety of is an antibody comprising a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 3 or SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5.
  • the L moiety of compound 3.1 comprises a heavy chain with at least 85% sequence identity to the first sequence and the light chain has at least 85% sequence identity to the second sequence.
  • the heavy chain has at least 90% sequence identity to the first sequence and the light chain has at least 90% sequence identity to the second sequence.
  • the heavy chain has at least 95% sequence identity to the first sequence and the light chain has at least 95% sequence identity to the second sequence. In some cases, the heavy chain has at least 98% sequence identity to the first sequence and the light chain has at least 98% sequence identity to the second sequence. In some cases, the heavy chain has at least 99% sequence identity to the first sequence and the light chain has at least 99% sequence identity to the second sequence. In some cases, the heavy chain comprises the first sequence and the light chain comprises the second sequence.
  • the L moiety of compound 3.1 comprises an antibody comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising at least 80% sequence identity to: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively (i.e., CDR-H1 has at least 80% sequence identity to SEQ ID NO: 13, CDR-H2 has at least 80% sequence identity to SEQ ID NO: 14, CDR-H3 has at least 80% sequence identity to SEQ ID NO: 15, CDR-L1 has at least 80% sequence identity to SEQ ID NO: 16, CDR-L2 has at least 80% sequence identity to SEQ ID NO: 17, and CDR-L3 has at least 80% sequence identity to SEQ ID NO: 18); SEQ ID NO: 21, 22, 23, 24, 25, and 26, respectively; SEQ ID NO: 38, 39, 40, 41, 42, and 43, respectively; SEQ ID NO: 49, 50, 51
  • the L moiety of compound 3.1 comprises an antibody that targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, and TIGIT.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising at least 80% sequence identity to: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NO: 77, 78, 79, 80, 81, and 82, , respectively; SEQ ID NO: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NO: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NO: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NO: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NO: 123, 124, 125, 126,
  • the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise at least 85% sequence identity to the respective 6 indicated sequences. In some cases, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprise at least 90% sequence identity to the respective 6 indicated sequences. In some cases, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprise at least 95% sequence identity to the respective 6 indicated sequences.
  • the CDR- H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprise at most one mutation relative to the respective 6 indicated sequences.
  • the L moiety of compound 3.1 comprises an antibody that binds to PDL1.
  • PDL1 is expressed in a broad range of cancers, as well as certain immune cells, and often serves as a primary mechanism for immune suppression in tumor microenvironments.
  • the PDL1 agonism of PD-1 can act as an immune checkpoint, diminishing lymphocyte tumor infiltration, and T-cell receptor mediated proliferation and signaling.
  • the compound 3.1 comprises an anti-PDL1 antibody comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18 respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively.
  • a Ligand-Drug Conjugate corresponding to compound 3.1 in Table 3 is provided wherein L comprises any of the anti-PDL1 antibodies described above or L comprises an amino acid sequence with at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, at least 98%, or at least 99% sequence identity an amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, or 18.
  • the L moiety of compound 3.1 comprises an antibody comprising a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 1-4 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5.
  • the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5.
  • the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5.
  • the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 3 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5.
  • the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 4 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5.
  • the L moiety of compound 3.1 comprises an antibody comprising a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 6-9 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 6 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 8 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 9 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10.
  • the L moiety of compound 3.1 comprises an antibody comprising a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 20.
  • the L moiety of compound 3.1 comprises an antibody that binds to EphA2.
  • the antibody comprises CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequences of SEQ ID NOs: 21, 22, 23, 24, 25, and 26, respectively.
  • the anti-EphA2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 28.
  • the anti-EphA2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of the amino acid sequence of SEQ ID NO: 31.
  • the anti-EphA2 antibody comprises a heavy chain comprising the amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 34.
  • the anti-EphA2 antibody comprises a heavy chain that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 35 or SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 37.
  • the antibody is h1C1 or 1C1.
  • the anti-EphA2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 28.
  • the L moiety of compond 3.1 comprises an antibody that binds to CD30.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively.
  • the anti-CD30 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 46 or 47 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 48.
  • the anti- CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 44 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 45.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD228.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively.
  • the anti-CD228 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 56.
  • the anti-CD228 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either of SEQ ID NO: 57 or 58 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 59.
  • the anti-CD228 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either of SEQ ID NO: 60 or 61 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 62.
  • the L moiety of compound 3.1 comprises an antibody that binds to avB6.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively.
  • the anti-H2A2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70.
  • the anti-H2A2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 71 or 72 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73.
  • the anti- H2A2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 74 or 75 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76.
  • the anti-avB6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70.
  • the anti-avB6 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 71 or 72 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73.
  • the anti- avB6 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 74 or 75 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76.
  • the L moiety of compound 3.1 comprises an antibody that binds to B7H4.
  • the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 77-82, SEQ ID NOs: 91-96, SEQ ID NOs: 99-104, SEQ ID NOs: 107-112, SEQ ID NOs: 115-120, SEQ ID NOs: 123-128, SEQ ID NOs: 131-136, SEQ ID NOs: 139-144, SEQ ID NOs: 147-152, SEQ ID NOs: 155-160, SEQ ID NOs: 163-168, SEQ ID NOs: 171-176, SEQ ID NOs: 179- 184, SEQ ID NOs: 187-192
  • the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively) each comprising at most one mutation relative to an amino acid sequence from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 77-82, SEQ ID NOs: 91-96, SEQ ID NOs: 99- 104, SEQ ID NOs: 107-112, SEQ ID NOs: 115-120, SEQ ID NOs: 123-128, SEQ ID NOs: 131-136, SEQ ID NOs: 139-144, SEQ ID NOs: 147-152, SEQ ID NOs: 155-160, SEQ ID NOs: 163-168, SEQ ID NOs: 171-176, SEQ ID NOs: 179-184, SEQ ID NOs: 187-192, SEQ ID NOs: 195-200, SEQ ID NOs: 203-208, SEQ ID NOs:
  • the anti-B7H4 antibody comprises a heavy chain and a light chain comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 85 and 87, SEQ ID NO: 86 and 87, SEQ ID NO: 88 and 90, SEQ ID NO: 89 and 90, SEQ ID NO: 251 and 252, , SEQ ID NO: 253 and 254, SEQ ID NO: 255 and 256, SEQ ID NO: 257 and 258, SEQ ID NO: 259 and 260, SEQ ID NO: 261 and 262, SEQ ID NO: 263 and 264, SEQ ID NO: 265 and 266, SEQ ID NO: 267 and 268, SEQ ID NO: 269 and 270, SEQ ID NO: 271 and 272, SEQ ID NO: 273 and 274, SEQ ID NO: 275 and 276, SEQ ID NO: 277
  • the anti-B7H4 antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 83 and 84, SEQ ID NO: 97 and 98, SEQ ID NO: 105 and 106, SEQ ID NO: 113 and 114, SEQ ID NO: 121 and 122, SEQ ID NO: 129 and 130, SEQ ID NO: 137 and 138, SEQ ID NO: 153 and 154, SEQ ID NO: 161 and 162, SEQ ID NO: 169 and 170, SEQ ID NO: 177 and 178, SEQ ID NO: 185 and 186, SEQ ID NO: 193 and 194, SEQ ID NO: 201 and 202, SEQ ID NO: 209 and 210, SEQ ID NO: 217 and 218, SEQ ID NO: 225
  • the L moiety of compound 3.1 comprises an antibody that binds to CD70.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively.
  • the anti-CD70 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 297 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 298.
  • the anti-CD70 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 299 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 300.
  • the L moiety of compound 3.1 comprises an antibody that binds to TROP2.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively.
  • an antibody provided herein binds to TROP2.
  • the antibody comprises CDR- H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 309, 310, 311, 312, 313, and 314 respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 309, 310, 311, 312, 313, and 314, respectively.
  • the anti-TROP2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 307 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 308.
  • the anti-TROP2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 315 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 316.
  • the L moiety of compound 3.1 comprises an antibody that binds to MICA.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively.
  • the anti- MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 323 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 324.
  • the anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 331 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 332.
  • the anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 340 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 340.
  • the anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 347 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 348.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD51.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively.
  • an antibody provided herein binds to CD51.
  • the antibody comprises CDR- H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 357, 358, 359, 360, 361, and 362, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 357, 358, 359, 360, 361, and 362, respectively.
  • the anti-CD51 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 355 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 356.
  • the anti-CD51 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 363 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 364.
  • the L moiety of compound 3.1 comprises an antibody that binds to gpA33.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 365, 366, 367, 368, 369, and 370, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 365, 366, 367, 368, 369, and 370, respectively.
  • the anti-gpA33 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 371 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 372.
  • the L moiety of compound 3.1 comprises an antibody that binds to IL1Rap.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively.
  • the anti-IL1Rap antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 379 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 380.
  • the L moiety of compound 3.1 comprises an antibody that binds to EpCAM.
  • the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 381-386, SEQ ID NOs: 389-394, SEQ ID NOs: 397-402, SEQ ID NOs: 405-410, SEQ ID NOs: 413- 418, or SEQ ID NOs: 421-426.
  • the anti-EpCAM antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 387 and 388, SEQ ID NO: 395 and 396, SEQ ID NO: 403 and 404, SEQ ID NO: 411 and 412, SEQ ID NO: 419 and 420, or SEQ ID NO: 427 and 428, respectively.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD352.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively.
  • the anti-CD352 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 435 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 436.
  • the L moiety of compound 3.1 comprises an antibody that binds to CS1.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively.
  • the anti-CS1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 443 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 444.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD38.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 445, 446, 447, 448, 449, and 450, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 445, 446, 447, 448, 449, and 450, respectively.
  • the anti-CD38 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 451 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 452.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD25.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively.
  • the anti-CD25 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 459 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 460.
  • the L moiety of compound 3.1 comprises an antibody that binds to ADAM9.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 469, 470, 471, 472, 473, and 474, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 469, 470, 471, 472, 473, and 474, respectively.
  • the anti-ADAM9 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 467 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 468.
  • the anti- ADAM9 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 475 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 476.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD59.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 477, 478, 479, 480, 481, and 482, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 477, 478, 479, 480, 481, and 482, respectively.
  • the anti-CD59 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 483 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 484.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD19.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 485, 486, 487, 488, 489, and 490, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 485, 486, 487, 488, 489, and 490, respectively.
  • the anti-CD19 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 491 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 492.
  • the anti-CD19 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 493 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 494.
  • the L moiety of compond 3.1 comprises an antibody that binds to CD138.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 495, 496, 497, 498, 499, and 500, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 495, 496, 497, 498, 499, and 500, respectively.
  • the anti-CD138 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 501 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 502.
  • the L moiety of compond 3.1 comprises an antibody that binds to CD166.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 503, 504, 505, 506, 507, and 508, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 503, 504, 505, 506, 507, and 508, respectively.
  • the anti-CD166 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 509 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 510.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD56.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively.
  • the anti-CD56 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 517 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 518.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD74.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 519, 520, 521, 522, 523, and 524, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 519, 520, 521, 522, 523, and 524, respectively.
  • the anti-CD74 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 525 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 526.
  • the L moiety of compound 3.1 comprises an antibody that binds to CEACAM5.
  • the antibody comprises CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 527, 528, 529, 530, 531, and 532, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 527, 528, 529, 530, 531, and 532, respectively.
  • the anti-CEACAM5 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 533 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 534.
  • the L moiety of compound 3.1 comprises an antibody that binds to CanAg.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively.
  • the anti-CanAg antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 541 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 542.
  • the L moiety of compound 3.1 comprises an antibody that binds to DLL-3.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 543, 544, 545, 546, 547, and 548, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 543, 544, 545, 546, 547, and 548, respectively.
  • the anti-DLL-3 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 549 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 550.
  • the L moiety of compound 3.1 comprises an antibody that binds to DPEP-3.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 551, 552, 553, 554, 555, and 556, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 551, 552, 553, 554, 555, and 556, respectively.
  • the anti-DPEP-3 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 557 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 558.
  • the L moiety of compound 3.1 comprises an antibody that binds to EGFR.
  • the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 559-564, SEQ ID NOs: 567-572, SEQ ID NOs: 575-580, and SEQ ID NOs: 895-900.
  • the anti-EGFR antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 565 and 566, SEQ ID NO: 573 and 574, SEQ ID NO: 581 and 582, or SEQ ID NO: 901 and 902, respectively.
  • the L moiety of compound 3.1 comprises an antibody that binds to FRa.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 583, 584, 585, 586, 587, and 588, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 583, 584, 585, 586, 587, and 588, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 591, 592, 593, 594, 595, and 596, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 591, 592, 593, 594, 595, and 596, respectively.
  • the anti-FRa antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 589 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 590.
  • the anti-FRa antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 597 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 598.
  • the L moiety of compound 3.1 comprises an antibody that binds to MUC-1.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 599, 600, 601, 602, 603, and 604, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 599, 600, 601, 602, 603, and 604, respectively.
  • the anti-MUC-1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 605 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 606.
  • the L moiety of compound 3.1 comprises an antibody that binds to Mesothelin.
  • the antibody comprises CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 607, 608, 609, 610, 611, and 612, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 607, 608, 609, 610, 611, and 612, respectively.
  • the anti-Mesothelin antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 613 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 614.
  • the L moiety of compound 3.1 comprises an antibody that binds to ROR-1.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 615, 616, 617, 618, 619, and 620, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 615, 616, 617, 618, 619, and 620, respectively.
  • the anti-ROR-1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 621 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 622.
  • the L moiety of compound 3.1 comprises an antibody that binds to B7H3.
  • the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 623-628, SEQ ID NOs: 631-636, SEQ ID NOs: 639-644, SEQ ID NOs: 647-652, SEQ ID NOs: 655- 660, SEQ ID NOs: 663-668, SEQ ID NOs: 671-676, SEQ ID NOs: 679-684, SEQ ID NOs: 687-692, SEQ ID NOs: 695-700, and SEQ ID NOs: 705-710.
  • the anti- B7H3 antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 629 and 630, SEQ ID NOs: 637 and 638, SEQ ID NOs: 645 and 646, SEQ ID NOs: 653 and 654, SEQ ID NOs: 661 and 662, SEQ ID NOs: 669 and 670, SEQ ID NOs: 677 and 678, SEQ ID NOs: 685 and 686, SEQ ID NOs: 693 and 694, SEQ ID NOs: 701 and 702, SEQ ID NOs: 703 and 704, SEQ ID NOs: 711 and 712, SEQ ID NOs: 713 and 714, and SEQ ID NOs: 715 and 716, respectively.
  • the L moiety of compound 3.1 comprises an antibody that binds to HER3.
  • the anti-HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 717 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 718.
  • an antibody provided herein binds to HER3.
  • the anti- HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 719 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 720.
  • an antibody provided herein binds to HER3.
  • the anti-HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 721 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 722.
  • an antibody provided herein binds to HER3.
  • the anti- HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 723 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 724.
  • the L moiety of compound 3.1 comprises an antibody that binds to PTK7.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 725, 726, 727, 728, 729, and 730, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 725, 726, 727, 728, 729, and 730, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 733, 734, 735, 736, 737, and 738, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 733, 734, 735, 736, 737, and 738, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 741, 742, 743, 744, 745, and 746, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 741, 742, 743, 744, 745, and 746, respectively.
  • the anti-PTK7 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 731 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 732.
  • the anti-PTK7 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 739 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 740.
  • the anti-PTK7 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 747 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 748.
  • the L moiety of compound 3.1 comprises an antibody that binds to ZIP6.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 749, 750, 751, 752, 753, and 754, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 749, 750, 751, 752, 753, and 754, respectively.
  • the anti-ZIP6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 755 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 756.
  • the anti-ZIP6 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 757 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 758.
  • the L moiety of compound 3.1 comprises an antibody that binds to Integrin ⁇ v ⁇ 6.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 759, 760, 761, 762, 763, and 764, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 759, 760, 761, 762, 763, and 764, respectively.
  • the anti- Integrin ⁇ v ⁇ 6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 765 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 766.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD48.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 767, 768, 769, 770, 771, and 772, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 767, 768, 769, 770, 771, and 772, respectively.
  • the anti-CD48 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 773 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 774.
  • the L moiety of compound 3.1 comprises an antibody that binds to IGF-1R.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 775, 776, 777, 778, 779, and 780, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 775, 776, 777, 778, 779, and 780, respectively.
  • the anti-IGF-1R antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 781 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 782.
  • the L moiety of compound 3.1 comprises an antibody that binds to Claudin-18.2.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 783, 784, 785, 786, 787, and 788, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 783, 784, 785, 786, 787, and 788, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 791, 792, 793, 794, 795, and 796, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 791, 792, 793, 794, 795, and 796, respectively.
  • the anti-Claudin-18.2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 789 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 790.
  • the anti-Claudin-18.2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 797 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 798.
  • the L moiety of compound 3.1 comprises an antibody that binds to Nectin-4.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 799, 800, 801, 802, 803, and 804, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 799, 800, 801, 802, 803, and 804, respectively.
  • the anti-Nectin-4 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 805 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 806.
  • the L moiety of compound 3.1 comprises an antibody that binds to SLTRK6.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 807, 808, 809, 810, 811, and 812, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 807, 808, 809, 810, 811, and 812, respectively.
  • the anti-SLTRK6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 813 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 814.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD142.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 815, 816, 817, 818, 819, and 820, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 815, 816, 817, 818, 819, and 820, respectively.
  • the anti-CD142 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 821 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 822.
  • the L moiety of compound 3.1 comprises an antibody that binds to Sialyl-Thomsen-nouveau antigen (STn).
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 823, 824, 825, 826, 827, and 828, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 823, 824, 825, 826, 827, and 828, respectively.
  • the anti-STn antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 829 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 830.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD20.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 831, 832, 833, 834, 835, and 836, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 831, 832, 833, 834, 835, and 836, respectively.
  • the anti-CD20 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 837 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 838.
  • the L moiety of compound 3.1 comprises an antibody that binds to HER2.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 839, 840, 841, 842, 843, and 844, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 839, 840, 841, 842, 843, and 844, respectively.
  • the anti-HER2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 845 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 846.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD79b.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 847, 848, 849, 850, 851, and 852, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 847, 848, 849, 850, 851, and 852, respectively.
  • the anti-CD79b antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 853 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 854.
  • the L moiety of compound 3.1 comprises an antibody that binds to NaPi2B.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 855, 856, 857, 858, 859, and 860, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 855, 856, 857, 858, 859, and 860, respectively.
  • the anti-NaPi2B antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 861 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 862.
  • the L moiety of compound 3.1 comprises an antibody that binds to Muc16.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 863, 864, 865, 866, 867, and 868, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 863, 864, 865, 866, 867, and 868, respectively.
  • the anti-Muc16 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 869 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 870.
  • the L moiety of compound 3.1 comprises an antibody that binds to STEAP1.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 871, 872, 873, 874, 875, and 876, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 871, 872, 873, 874, 875, and 876, respectively.
  • the anti-STEAP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 877 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 878.
  • the L moiety of compound 3.1 comprises an antibody that binds to BCMA.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 879, 880, 881, 882, 883, and 884, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 879, 880, 881, 882, 883, and 884, respectively.
  • the anti-BCMA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 885 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 886.
  • the L moiety of compound 3.1 comprises an antibody that binds to c-Met.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 887, 888, 889, 890, 891, and 892, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 887, 888, 889, 890, 891, and 892, respectively.
  • the anti-c-Met antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 893 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 893.
  • the L moiety of compound comprises an antibody that binds to SLAMF7.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 903, 904, 905, 906, 907, and 908, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 903, 904, 905, 906, 907, and 908, respectively.
  • the anti-SLAMF7 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 909 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 910.
  • the L moiety of compound 3.1 comprises an antibody that binds to C4.4a.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 911, 912, 913, 914, 915, and 916, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 911, 912, 913, 914, 915, and 916, respectively.
  • the anti-C4.4a antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 917 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 918.
  • the L moiety of compound 3.1 comprises an antibody that binds to GCC.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 919, 920, 921, 922, 923, and 924, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 919, 920, 921, 922, 923, and 924, respectively.
  • the anti-GCC antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 925 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 926.
  • the L moiety of compound 3.1 comprises an antibody that binds to Axl.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 927, 928, 929, 930, 931, and 932, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 927, 928, 929, 930, 931, and 932, respectively.
  • the anti-Axl antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 933 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 933.
  • the L moiety of compound 3.1 comprises an antibody that binds to transmembrane glycoprotein NMB (gpNMB).
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 935, 936, 937, 938, 939, and 940, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 935, 936, 937, 938, 939, and 940, respectively.
  • the anti-gpNMB antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 941 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 942.
  • the anti-gpNMB antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 943 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 944.
  • the L moiety of compound 3.1 comprises an antibody that binds to Prolactin receptor.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 945, 946, 947, 948, 949, and 950, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 945, 946, 947, 948, 949, and 950, respectively.
  • the anti-Prolactin receptor antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 951 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 952.
  • the L moiety of compound 3.1 comprises an antibody that binds to FGFR2.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 953, 954, 955, 956, 957, and 958, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 953, 954, 955, 956, 957, and 958, respectively.
  • the anti-FGFR2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 959 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 960.
  • the L moiety of compound 3.1 comprises an antibody that binds to CDCP1.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 961, 962, 963, 964, 965, and 966, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 969, 970, 971, 972, 973, and 974, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 961, 962, 963, 964, 965, and 966, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 969, 970, 971, 972, 973, and 974, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 977, 978, 979, 980, 981, and 982, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 977, 978, 979, 980, 981, and 982, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 985, 986, 987, 988, 989, and 990, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 985, 986, 987, 988, 989, and 990, respectively.
  • the anti- CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 967 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 968.
  • the anti-CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 975 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 976.
  • the anti-CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 983 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 984.
  • the anti-CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 991 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 992.
  • the L moiety of compound 3.1 comprises an antibody that binds to ASCT2.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 997, 998, 999, 1000, 1001, and 1002, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 997, 998, 999, 1000, 1001, and 1002, respectively.
  • the anti-ASCT2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 993 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 994.
  • the anti-ASCT2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 995 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 996.
  • the anti-ASCT2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1003 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1004.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD123.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1005, 1006, 1007, 1008, 1009, and 1010, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1005, 1006, 1007, 1008, 1009, and 1010, respectively.
  • the anti-CD123 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1011 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1012.
  • the L moiety of compound 3.1 comprises an antibody that binds to GPC3.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1013, 1014, 1015, 1016, 1017, and 1018 respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1013, 1014, 1015, 1016, 1017, and 1018, respectively.
  • the anti-TIGIT antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1027 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1028.
  • the L moiety of compound 3.1 comprises an antibody that binds to TIGIT.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively.
  • the anti-BCMA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1043 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1044.
  • the L moiety of compound 3.1 comprises an antibody that binds to CD33.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1029, 1030, 1031, 1032, 1033, and 1034, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1029, 1030, 1031, 1032, 1033, and 1034, respectively.
  • the anti-CD33 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1035 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1036.
  • the L moiety of compound 3.1 comprises an antibody that binds to BCMA.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1037, 1038, 1039, 1040, 1041, and 1042, respectively.
  • the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1037, 1038, 1039, 1040, 1041, and 1042, respectively.
  • the anti-BCMA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1043 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1044.
  • references to a compound of Formula (I), (I'), (I*), (II), or any subformula thereof includes all subgroups of Formula (I), (I'), (I*), (II), or any subformula thereof, defined herein, including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and/or described herein.
  • references to a compound of Formula (I), (I'), (I*), (II), or any subformula thereof include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and/or protected forms thereof.
  • references to a compound of Formula (I), (I'), (I*), (II), or any subformula thereof include polymorphs, solvates, co-crystals, isomers, tautomers and/or oxides thereof.
  • references to a compound of Formula (I), (I'), (I*), (II), or any subformula thereof include polymorphs, solvates, and/or co-crystals thereof.
  • references to a compound of Formula (I), (I'), (I*), (II), or any subformula thereof include isomers, tautomers and/or oxides thereof.
  • references to a compound of Formula (I), (I'), (I*), (II), or any subformula thereof include solvates thereof.
  • the term “salts” includes solvates of salts of compounds.
  • any formula given herein such as Formula (I), (I'), (I*), (II), or any subformula thereof, is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms.
  • compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula.
  • any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio.
  • a compound of one of Tables 1, 2, or 3 is depicted with a particular stereochemical configuration, also provided herein is any alternative stereochemical configuration of the compound, as well as a mixture of stereoisomers of the compound in any ratio.
  • a compound of Tables 1, 2, or 3 has a stereocenter that is in an “S” stereochemical configuration
  • enantiomer of the compound wherein that stereocenter is in an “R” stereochemical configuration is enantiomer of the compound wherein that stereocenter is in an “R” stereochemical configuration.
  • a compound of Tables 1, 2, or 3 has a stereocenter that is in an “R” configuration
  • enantiomer of the compound in an “S” stereochemical configuration also provided are mixtures of the compound with both the “S” and the “R” stereochemical configuration.
  • a compound of Tables 1, 2, or 3 has two or more stereocenters
  • any enantiomer or diastereomer of the compound if a compound of Tables 1, 2, or 3 contains a first stereocenter and a second stereocenter with “R” and “R” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “S” and “S” stereochemical configurations, respectively, “S” and “R” stereochemical configurations, respectively, and “R” and “S” stereochemical configurations, respectively.
  • a compound of Tables 1, 2, or 3 contains a first stereocenter and a second stereocenter with “S” and “S” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “R” and “R” stereochemical configurations, respectively, “S” and “R” stereochemical configurations, respectively, and “R” and “S” stereochemical configurations, respectively.
  • a compound of Tables 1, 2, or 3 contains a first stereocenter and a second stereocenter with “S” and “R” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “R” and “S” stereochemical configurations, respectively, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively.
  • a compound of Tables 1, 2, or 3 contains a first stereocenter and a second stereocenter with “R” and “S” stereochemical configurations, respectively
  • certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers.
  • any formula given herein is intended to refer also to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly.
  • the solvent is water and the solvates are hydrates.
  • the compounds depicted herein may be present as salts even if salts are not depicted, and it is understood that the compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan.
  • the salts of the compounds provided herein are pharmaceutically acceptable salts.
  • Embodiments are contemplated wherein any variation or embodiment of Q, D, Z or Z', A, B, S*, RL, Y, W, L, Z a , X b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R a , R b , E, X, subscript n, subscript n, subscript q, and/or subscript p provided herein is combined with every other variation or embodiment of Q, D, Z or Z', A, B, S*, RL, Y, W, L, Z a , X b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R a , R b , E, X, subscript n, subscript n, subscript q, and/or
  • any of the compounds described herein such as a compound of Formula (I), (I'), (I*), (II), or any subformula thereof, or a compound of any one of Tables 1, 2 or 3, or a salt of any of the foregoing, may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom).
  • the compound is deuterated at a single site.
  • the compound is deuterated at multiple sites.
  • Deuterated compounds are sometimes prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds.
  • hydrogen atoms are be replaced with deuterium atoms using other methods known in the art.
  • gpNMB is a type 1 transmembrane protein that has been shown to be pro- metastatic, and high expression is correlated with worse cancer patient survival. Taya et al., Steroids, 2017, 133:102. It is expressed in many cancer indications, including melanoma, squamous non-small-cell lung cancer (sqNSCLC), Head and Neck, and esophageal cancers.
  • gpNMB-targeted antibody-drug conjugate would pair well with a payload with an improved therapeutic index.
  • ligand-drug conjugates such as of compound 3.1, wherein the L moiety is an anti-gpNMB antibody, or antigen-binding fragment thereof.
  • the antibody, or antigen-binding fragment thereof in some embodiments bind to gpNMB with an affinity (e.g., EC 50 ) of less than 10 nM, 5 nM, 2 nM, 1 nM, 500 pM, 250 pM, 100 pM, 50 pM, 25 pM, 10 pM, or 1 pM. In some embodiments, the antibody, or antigen-binding fragment thereof, binds to gpNMB with an affinity of between 5-10 nM, 1-5 nM, 500 pM – 1 nM, 100 – 250 pM, 50 – 100 pM, 10-50 pM, or 1-10 pM.
  • an affinity e.g., EC 50
  • the antibody, or antigen-binding fragment thereof comprises the CDRs, the varianble domains, and/or the heavy and light chain amino acid sequences as indicated in Table D1 and D2, below.
  • Table D1 Exemplary anti-gpNMB antibody CDR sequences.
  • Table D2. Exemplary anti-gpNMB variable domain, light chain, and heavy chain sequences.
  • Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise the 6 CDRs as follows: a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising the amino acid sequences of SEQ ID NOs:935-940, respectively.
  • Some of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise a VH comprising the amino acid sequence of SEQ ID NO:941 and a VL comprising the amino acid sequence of SEQ ID NO:942.
  • Some of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise a HC comprising the amino acid sequence of SEQ ID NO:943 and a LC comprising the amino acid sequence of SEQ ID NO:944.
  • the antibody, or antigen-binding fragment thereof, that are provided include or are derived from one or more of the CDRs, variable heavy chains, variable light chains, heavy chains, and/or light chains of the antibodies listed in Tables D1 and D2, or variants or derivatives thereof.
  • Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise the 6 CDRs as follows: a CDR-H1, a CDR-H2, a CDR-H3 from the variable heavy chain sequence comprising the amino acid sequence of SEQ ID NO:941, and a CDR-L1, a CDR-L2, and a CDR-L3 from the variable light chain sequence comprising the amino acid sequence of SEQ ID NO:942, wherein the CDRs are defined by the IMGT CDR numbering scheme.
  • Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise the 6 CDRs as follows: a CDR-H1, a CDR-H2, a CDR-H3 from the variable heavy chain sequence comprising the amino acid sequence of SEQ ID NO:941, and a CDR-L1, a CDR-L2, and a CDR-L3 from the variable light chain sequence comprising the amino acid sequence of SEQ ID NO:942, wherein the CDRs are defined by the Kabat CDR numbering scheme.
  • Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise the 6 CDRs as follows: a CDR-H1, a CDR-H2, a CDR-H3 from the variable heavy chain sequence comprising the amino acid sequence of SEQ ID NO:941, and a CDR-L1, a CDR-L2, and a CDR-L3 from the variable light chain sequence comprising the amino acid sequence of SEQ ID NO:942, wherein the CDRs are defined by the AbM CDR numbering scheme.
  • Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise the 6 CDRs as follows: a CDR-H1, a CDR-H2, a CDR-H3 from the variable heavy chain sequence comprising the amino acid sequence of SEQ ID NO:941, and a CDR-L1, a CDR-L2, and a CDR-L3 from the variable light chain sequence comprising the amino acid sequence of SEQ ID NO:942, wherein the CDRs are defined by the Chothia CDR numbering scheme.
  • Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise the 6 CDRs as follows: a CDR-H1, a CDR-H2, a CDR-H3 from the variable heavy chain sequence comprising the amino acid sequence of SEQ ID NO:941, and a CDR-L1, a CDR-L2, and a CDR-L3 from the variable light chain sequence comprising the amino acid sequence of SEQ ID NO:942, wherein the CDRs are defined by the Contact CDR numbering scheme.
  • Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise a VH comprising a CDR-H1, a CDR-H2, and a CDR-H3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDR-H1 reference sequence has the amino acid sequence of SEQ ID NO:935, the CDR-H2 reference sequence has the amino acid sequence of SEQ ID NO:936, and the CDR-H3 reference sequence has the amino acid sequence of SEQ ID NO:937.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions.
  • Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise a VL comprising a CDR-L1, a CDR-L2, and a CDR-L3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDR-L1 reference sequence has the amino acid sequence of SEQ ID NO:938, the CDR-L2 reference sequence has the amino acid sequence of SEQ ID NO:939, and the CDR-L3 reference sequence has the amino acid sequence of SEQ ID NO:940.
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise a VH comprising a CDR-H1, a CDR-H2, and a CDR-H3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDR-H1 reference sequence has the amino acid sequence of SEQ ID NO:935, the CDR-H2 reference sequence has the amino acid sequence of SEQ ID NO:936, and the CDR-H3 reference sequence has the amino acid sequence of SEQ ID NO:937; and a VL comprising a CDR-L1, a CDR-L2, and a CDR-L3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDR-L1 reference sequence has the amino acid sequence of SEQ ID NO:938, the CDR-L2 reference sequence has the amino acid sequence
  • the amino acid changes typically are insertions, deletions and/or substitutions.
  • the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2.
  • the changes are conservative amino acid substitutions.
  • the antibody, or antigen-binding fragment thereof comprises a VH domain, wherein the VH domain sequence has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:941, provided the antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB.
  • such an antibody, or antigen- binding fragment thereof contains substitutions (e.g., conservative substitutions), insertions, and/or deletions relative to the reference sequence (i.e., SEQ ID NO:941), provided that such an antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB.
  • substitutions e.g., conservative substitutions
  • insertions e.g., insertions, and/or deletions relative to the reference sequence (i.e., SEQ ID NO:941), provided that such an antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:941.
  • 1-5 or 1-3 amino acids have been substituted, inserted and/or deleted in the VH sequence.
  • substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the framework regions).
  • the antibody, or antigen-binding fragment thereof comprises a VL domain, wherein the VL domain sequence has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:942, provided the antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB.
  • such an antibody, or antigen-binding fragment thereof contains substitutions (e.g., conservative substitutions), insertions, and/or deletions relative to the reference sequence (i.e., SEQ ID NO:942), provided that such an antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB.
  • substitutions e.g., conservative substitutions
  • insertions e.g., insertions, and/or deletions relative to the reference sequence (i.e., SEQ ID NO:942), provided that such an antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB.
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:942.
  • 1-5 or 1-3 amino acids have been substituted, inserted and/or deleted in the VL sequence.
  • substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the framework regions).
  • the antibody, or antigen-binding fragment thereof comprises: a VH domain, wherein the VH domain sequence has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:941, provided the antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB; and a VL domain, wherein the VL domain sequence has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:942, provided the antibody, or antigen- binding fragment thereof, retains the ability to bind to gpNMB.
  • such an antibody, or antigen-binding fragment thereof contains substitutions (e.g., conservative substitutions), insertions, and/or deletions relative to the reference sequence (i.e., SEQ ID NO:941 for the VH domain and SEQ ID NO:942 for the VL domain), provided that such an antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB.
  • substitutions e.g., conservative substitutions
  • insertions, and/or deletions relative to the reference sequence i.e., SEQ ID NO:941 for the VH domain and SEQ ID NO:942 for the VL domain
  • an antibody, or antigen-binding fragment thereof comprises an HC comprising the amino acid sequence of SEQ ID NO:943, and a LC comprising the amino acid sequence of SEQ ID NO:944.
  • the antibody, or antigen-binding fragment thereof, as described herein can be an antibody in any form.
  • the antibody, or antigen-binding fragment thereof, described in any of the above embodiments can be monoclonal, and may be multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab') fragments, fragments produced by a Fab expression library, and gpNMB-binding fragments of any of the above.
  • the antibodies can be of any immunoglobulin isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass.
  • an antibody, or antigen-binding fragment thereof, with the CDRs and/or variable domain sequences described herein is an antigen-binding fragment (e.g., human antigen-binding fragments) including, but are not limited to, Fab, Fab' and F(ab') 2 , Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain.
  • the antibody, or antigen-binding fragment thereof can be monospecific or part of a bispecific or trispecific antibody, or antigen-binding fragments thereof, or part of an antibody, or antigen-binding fragment thereof, of greater multi-specificity.
  • Multispecific antibodies can be specific for different epitopes of gpNMB or may be specific for both gpNMB and a heterologous protein.
  • the antibodies, or antigen-binding fragments thereof, in any of the foregoing embodiments can be an antibody in any form.
  • the antibody, or antigen-binding fragment thereof, described in any of the above embodiments can be, for example, a monoclonal antibody, a multispecific antibody, a human, humanized or chimeric antibody, and gpNMB binding fragments of any of the above, such as a single chain antibody, an Fab fragment, an F(ab') fragment, or a fragment produced by a Fab expression library.
  • the antibodies can be of any immunoglobulin isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass.
  • a antibody, or antigen-binding fragment thereof, with the CDR and/or variable domain sequences described herein is an antigen-binding fragment (e.g., human antigen-binding fragments) and include, but are not limited to, Fab, Fab' and F(ab') 2 , Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain.
  • Antigen-binding fragments, including single-chain antibodies may comprise the variable region(s) alone or in combination with the entirety or a portion of the following: hinge region, CH1, CH 2 , CH 3 and CL domains.
  • antigen-binding fragments comprising any combination of variable region(s) with a hinge region, CH1, CH 2 , CH 3 and CL domains.
  • the antibody, or antigen-binding fragment thereof can be monospecific, bispecific, trispecific or of greater multi specificity. Multispecific antibodies can be specific for different epitopes of gpNMB or may be specific for both gpNMB as well as for a heterologous protein. See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., 1991, J. Immunol. 147:6069; U.S. Pat.
  • one or several amino acids e.g., 1, 2, 3 or 4
  • amino acids at the amino or carboxy terminus of the light and/or heavy chain, such as the C- terminal lysine of the heavy chain, may be missing or derivitized in some or all of the molecules in a composition.
  • an antibody, or antigen-binding fragment thereof in which the carboxy terminal lysine of the heavy chain is missing (e.g., as part of a post-translational modification).
  • any of the sequences described herein include post-translational modifications to the specified sequence during expression of the antibody, or antigen-binding fragment thereof, in cell culture (e.g., a CHO cell culture).
  • the moiety L of compound 3.1 is not an antibody or antigen-binding fragment thereof but instead comprises a non-antibody scaffold into which one or more CDRs (e.g., 1, 2, 3, 4, 5 or 6) and/or one or more variable domains as described herein is grafted, inserted, and/or joined.
  • Chimeric Antibody, or an Antigen-Binding Fragment thereof is a chimeric antibody.
  • a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region.
  • a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Certain chimeric antibodies are described, e.g., in U.S. Patent No. 4,816,567; and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA, 81 :6851-6855 (1984)). Chimeric antibodies include antigen-binding fragments thereof.
  • Nonlimiting exemplary chimeric antibodies include chimeric antibodies comprising any of the heavy and/or light chain variable regions as described herein. Additional nonlimiting exemplary chimeric antibodies include chimeric antibodies comprising heavy chain CDR sequences or portions thereof, and/or light chain CDR sequences as provided herein.
  • Humanized Antibody, or antigen-binding fragment thereof [0659] In certain embodiments, the antibody, or antigen-binding fragment thereof, is a humanized antibody, or antigen-binding fragment thereof, that binds gpNMB.
  • a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody.
  • a humanized antibody is a genetically engineered antibody in which the CDRs or portions thereof from a non-human “donor” antibody are grafted into human “acceptor” antibody sequences (see, e.g., Queen, US 5,530,101 and 5,585,089; Winter, US 5,225,539; Carter, US 6,407,213; Adair, US 5,859,205; and Foote, US 6,881,557).
  • the acceptor antibody sequences can be, for example, a mature human antibody sequence, a composite of such sequences, a consensus sequence of human antibody sequences, or a germline region sequence.
  • Human acceptor sequences can be selected for a high degree of sequence identity in the variable region frameworks with donor sequences to match canonical forms between acceptor and donor CDRs among other criteria.
  • a humanized antibody is an antibody having CDRs entirely or substantially from a donor antibody and variable region framework sequences and constant regions, if present, entirely or substantially from human antibody sequences.
  • a humanized heavy chain typically has all three CDRs entirely or substantially from a donor antibody heavy chain, and a heavy chain variable region framework sequence and heavy chain constant region, if present, substantially from human heavy chain variable region framework and constant region sequences.
  • a humanized light chain usually has all three CDRs entirely or substantially from a donor antibody light chain, and a light chain variable region framework sequence and light chain constant region, if present, substantially from human light chain variable region framework and constant region sequences.
  • a CDR in a humanized antibody is substantially from a corresponding CDR in a non-human antibody when at least 80%, 85%, 90%, 95% or 100% of corresponding residues (such as defined by Kabat) are identical between the respective CDRs.
  • the variable region framework sequences of an antibody chain or the constant region of an antibody chain are substantially from a human variable region framework sequence or human constant region respectively when at least 80%, 85%, 90%, 95% or 100% of corresponding residues, such as defined by Kabat, are identical.
  • the human framework amino acid when an amino acid differs between a murine variable region framework residue and a selected human variable region framework residue, the human framework amino acid can be substituted by the equivalent framework amino acid from the mouse antibody when it is reasonably expected that the amino acid: (1) noncovalently binds antigen directly, (2) is adjacent to a CDR region, (3) otherwise interacts with a CDR region (e.g., is within about 6 ⁇ of such a region); (4) mediates interaction between the heavy and light chains, or (5) is the result of somatic mutation in the mouse chain. (6) is a site of glycosylation.
  • Framework residues from classes (1)-(3) are sometimes alternately referred to as canonical and vernier residues.
  • Canonical residues refer to framework residues defining the canonical class of the donor CDR loops determining the conformation of a CDR loop (Chothia and Lesk, J. Mol. Biol. 196, 901-917 (1987), Thornton & Martin, J. Mol. Biol., 263, 800-815, 1996).
  • Vernier residues refer to a layer of framework residues that support antigen- binding loop conformations and play a role in fine-tuning the fit of an antibody to antigen (Foote & Winter, 1992, J Mol Bio. 224, 487-499).
  • Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. (1993) J. Immunol.
  • framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions see, e.g., Carter et al. (1992) Proc. Natl. Acad. Sci. USA, 89:4285; and Presta et al. (1993) J. Immunol, 151:2623); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, (2008) Front. Biosci. 13:1619-1633); and framework regions derived from screening FR libraries (see, e.g., Baca et al., (1997) J. Biol. Chem.
  • Non-limiting exemplary chimeric antibodies include chimeric antibodies comprising or derived from any of the CDR and/or heavy chain variable region and/or light chain variable regions as disclosed herein. .
  • humanized antibodies often incorporate all six HVRs (e.g., CDRs, preferably as defined by Kabat) from a mouse antibody, they can also be made with less than all HVRs or CDRs (e.g., at least 3, 4, or 5) HVRs or CDRs from a mouse antibody (e.g., Pascalis et al., J. Immunol.
  • Certain amino acids from the human variable region framework residues can be selected for substitution based on their possible influence on HVR (e.g,.CDR) conformation and/or binding to antigen. Investigation of such possible influences is by modeling, examination of the characteristics of the amino acids at particular locations, or empirical observation of the effects of substitution or mutagenesis of particular amino acids.
  • HVR e.g,.CDR
  • the heavy and light chain variable regions of antibodies, or antigen-binding fragments thereof, described herein can be linked to at least a portion of a human constant region.
  • the human heavy chain constant region is of an isotype selected from IgA, IgG, and IgD.
  • the human light chain constant region is of an isotype selected from ⁇ and ⁇ .
  • an antibody described herein comprises a human IgG constant region.
  • an antibody described herein comprises a human IgG4 heavy chain constant region.
  • an antibody described herein comprises an S241P mutation in the human IgG4 constant region.
  • an antibody described herein comprises a human IgG4 constant region and a human ⁇ light chain.
  • the numbering of the residues in an immunoglobulin heavy chain is that of the EU index as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), expressly incorporated herein by reference.
  • the “EU index as in Kabat” refers to the residue numbering of the human IgG1 EU antibody.
  • Human constant regions show allotypic variation and isoallotypic variation between different individuals, that is, the constant regions can differ in different individuals at one or more polymorphic positions. Isoallotypes differ from allotypes in that sera recognizing an isoallotype binds to a non-polymorphic region of a one or more other isotypes. Reference to a human constant region includes a constant region with any natural allotype or any permutation of residues occupying polymorphic positions in natural allotypes. Also, up to 1, 2, 5, or 10 mutations may be present relative to a natural human constant region, such as those indicated above to reduce Fc ⁇ receptor binding or increase binding to FcRn.
  • one or several amino acids at the amino or carboxy terminus of the light and/or heavy chain may be missing or derivatized in a proportion or all of the molecules.
  • the choice of constant region depends, in part, whether antibody-dependent cell- mediated cytotoxicity, antibody dependent cellular phagocytosis and/or complement dependent cytotoxicity are desired.
  • human isotopes IgG1 and IgG3 have strong complement-dependent cytotoxicity
  • human isotype IgG2 weak complement-dependent cytotoxicity
  • human IgG4 lacks complement-dependent cytotoxicity.
  • Human IgG1 and IgG3 also induce stronger cell-mediated effector functions than human IgG2 and IgG4.
  • Light chain constant regions can be lambda or kappa.
  • substitutions can be made in the constant regions to reduce or increase effector function such as complement-mediated cytotoxicity or ADCC (see, e.g., Winter et al., US Patent No. 5,624,821; Tso et al., US Patent No. 5,834,597; and Lazar et al., Proc. Natl. Acad. Sci. USA 103:4005, 2006), or to prolong half-life in humans (see, e.g., Hinton et al., J. Biol. Chem.
  • the antibodies, or antigen-binding fragments thereof, provided herein also include amino acid sequence variants of the antibody, or antigen-binding fragment thereof, provided herein such as those described in Table D1 and D2.
  • variants with improved binding affinity and/or other biological properties of the antibody can be prepared.
  • Amino acid sequence variants of an antigen binding protein can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antigen binding protein, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antigen binding protein.
  • an antibody, or antigen-binding fragment thereof is a variant in that it has one or more amino acid substitutions, deletions and/or insertions relative to an antibody, or antigen-binding fragment thereof, as described herein (e.g., an antibody, or antigen-binding fragment thereof, having the amino acid sequences as described in Tables D1 and D2.
  • the variant has one or more amino acid substitutions.
  • the substitutions are conservative amino acid substitutions.
  • amino acid substitution can include but are not limited to the replacement of one amino acid in a polypeptide with another amino acid.
  • Conservative amino acid substitutions can encompass non-naturally occurring amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems.
  • Naturally occurring residues can be divided into classes based on common side chain properties. (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe.
  • Sites of interest for substitutional mutagenesis include the CDRs and framework regions. Conservative substitutions are shown in Table D3, below, under the heading of "Preferred Substitutions.” More substantial changes are provided in Table D3 under the heading of "Exemplary Substitutions," and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC. Table D3. Conservative and Exemplary Amino Acid Substitutions. [0678] Non-conservative substitutions involve exchanging a member of one of these classes for another class.
  • the hydropathic index of amino acids can be considered.
  • Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics as follows: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (- 0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5).
  • substitution of like amino acids can be made effectively on the basis of hydrophilicity, particularly where the biologically functional protein or peptide (e.g., antibody) thus created is intended for use in immunological embodiments, as in the present case.
  • the greatest local average hydrophilicity of a protein as governed by the hydrophilicity of its adjacent amino acids, correlates with its immunogenicity and antigenicity, i.e., with a biological property of the protein.
  • hydrophilicity values have been assigned to these amino acid residues: arginine (+3.0); lysine (+3.0 ⁇ 1); aspartate (+3.0 ⁇ 1); glutamate (+3.0 ⁇ 1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5 ⁇ 1); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5) and tryptophan (-3.4).
  • the substitution of amino acids whose hydrophilicity values are within ⁇ 2 is included, in certain embodiments, those which are within ⁇ 1 are included, and in certain embodiments, those within ⁇ 0.5 are included.
  • Alterations e.g., substitutions
  • Such alterations can be made in CDR "hotspots," i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or residues that contact antigen, with the resulting variant VH or VL being tested for binding affinity.
  • Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al.
  • variable genes chosen for maturation are introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis).
  • a secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity.
  • Another method to introduce diversity involves hypervariable region (HVR)- directed approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized.
  • HVR hypervariable region
  • HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.
  • substitutions, insertions, or deletions can occur within one or more CDRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen.
  • conservative alterations e.g., conservative substitutions as provided herein
  • Such alterations may, for example, be outside of antigen contacting residues in the CDRs.
  • each CDR either is unaltered, or contains no more than one, two or three amino acid substitutions.
  • a useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called "alanine scanning mutagenesis" as described by Cunningham and Wells (1989) Science, 244:1081-1085.
  • a residue or group of target residues e.g., charged residues such as arg, asp, his, lys, and glu
  • a neutral or negatively charged amino acid e.g., alanine or polyalanine
  • Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue.
  • Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Pat. No. 6,737,056).
  • Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called "DANA" Fc mutant with substitution of residues 265 and 297 to alanine (U.S.
  • an antibody variant is prepared that has improved or diminished binding to FcRs are described. (See, e.g., U.S. Pat. No. 6,737,056; WO 2004/056312, and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001).)
  • an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues).
  • IgG variants with altered Fc ⁇ R binding affinities (Shields et al., 2001, J. Biol. Chem. 276:6591-604).
  • a subset of these variants involving substitutions at Thr256/Ser298, Ser298/Glu333, Ser298/Lys334, or Ser298/Glu333/Lys334 to Ala demonstrate increased in both binding affinity toward Fc ⁇ R and ADCC activity (Shields et al., 2001, J. Biol. Chem. 276:6591-604; Okazaki et al., 2004, J. Mol. Biol.
  • alterations are made in the Fc region to alter (i.e., either improved or diminished) Clq binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000).
  • CDC Complement Dependent Cytotoxicity
  • complement fixation activity of antibodies can be improved by substitutions at Lys326 and Glu333 (Idusogie et al., 2001, J. Immunol. 166:2571-2575).
  • alkyl-substituted non-ionic residues such as Gly, Ile, Leu, or Val, or such aromatic non-polar residues as Phe, Tyr, Trp and Pro in place of any one of the three residues also reduce or abolish C1q binding.
  • Ser, Thr, Cys, and Met can be used at residues 320 and 322, but not 318, to reduce or abolish C1q binding activity.
  • Replacement of the 318 (Glu) residue by a polar residue may modify but not abolish C1q binding activity.
  • Replacing residue 297 (Asn) with Ala results in removal of lytic activity but only slightly reduces (about three fold weaker) affinity for C1q.
  • FcRn is a receptor that is structurally similar to MHC Class I antigen that non-covalently associates with ⁇ 2-microglobulin. FcRn regulates the catabolism of IgGs and their transcytosis across tissues (Ghetie and Ward, 2000, Annu. Rev. Immunol.
  • the IgG-FcRn interaction takes place at pH 6.0 (pH of intracellular vesicles) but not at pH 7.4 (pH of blood); this interaction enables IgGs to be recycled back to the circulation (Ghetie and Ward, 2000, Ann. Rev. Immunol. 18:739-766; Ghetie and Ward, 2002, Immunol. Res. 25:97-113).
  • the region on human IgG1 involved in FcRn binding has been mapped (Shields et al., 2001, J. Biol. Chem. 276:6591-604).
  • IgG1 Alanine substitutions at positions Pro238, Thr256, Thr307, Gln311, Asp312, Glu380, Glu382, or Asn434 of human IgG1 enhance FcRn binding (Shields et al., 2001, J. Biol. Chem. 276:6591-604). IgG1 molecules harboring these substitutions have longer serum half-lives. Consequently, these modified IgG 1 molecules may be able to carry out their effector functions, and hence exert their therapeutic efficacies, over a longer period of time compared to unmodified IgG1.
  • Other exemplary substitutions for increasing binding to FcRn include a Gln at position 250 and/or a Leu at position 428.
  • Fc region residues 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (see, e.g., U.S. Pat. No. 7,371,826; and US 7,361,740).
  • an antibody, or antigen-binding fragment thereof, as provided herein includes one or more modifications so as to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody can be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed.
  • the antibody comprises an Fc region
  • the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH 2 domain of the Fc region. See, e.g., Wright et al.
  • the oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the "stem" of the biantennary oligosaccharide structure.
  • GlcNAc N-acetyl glucosamine
  • galactose galactose
  • sialic acid sialic acid
  • antibodies having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region.
  • the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%.
  • the amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e.g., complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example.
  • Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ⁇ 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd).
  • Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng.
  • Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application No. US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially at Example 11), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol.
  • antibodies are further provided which contain bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibodies may have reduced fucosylation and/or improved ADCC function. Examples of such antibodies are described, e.g., in WO 2003/011878 (Jean- Mairet et al.); US Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.).
  • Antibodies with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.).
  • an antibody variant as provided herein includes a substitution of the native amino acid to a cysteine residue at amino acid position 234, 235, 237, 239, 267, 298, 299, 326, 330, or 332, preferably an S239C mutation (substitutions of the constant regions are according to the EU index) in a human IgG1 isotype.
  • an S239C mutation substitutions of the constant regions are according to the EU index
  • the presence of an additional cysteine residue allows interchain disulfide bond formation. Such interchain disulfide bond formation can cause steric hindrance, thereby reducing the affinity of the Fc region-Fc ⁇ R binding interaction.
  • the cysteine residue(s) introduced in or in proximity to the Fc region of an IgG constant region can also serve as sites for conjugation to therapeutic agents (e.g., coupling cytotoxic drugs using thiol specific reagents such as maleimide derivatives of drugs).
  • therapeutic agents e.g., coupling cytotoxic drugs using thiol specific reagents such as maleimide derivatives of drugs.
  • the presence of a therapeutic agent causes steric hindrance, thereby further reducing the affinity of the Fc region-Fc ⁇ R binding interaction.
  • one or more reactive thiol groups are positioned at accessible sites of the antibody and can be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein.
  • any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and 5400 (EU numbering) of the heavy chain Fc region.
  • Generating of cysteine engineered antibodies are described, e.g., in U.S. Pat. No. 7,521,541. Competing Antibody, or Antigen-Binding Fragments thereof [0699]
  • the antibodies, or antigen-binding fragments thereof, provided herein include those that compete with one of the exemplified antibodies, or antigen-binding fragment thereof, for specific binding, such as to gpNMB, such as human gpNMB.
  • the test and reference antibody, or antigen-binding fragment thereof cross- compete with one another.
  • Such an antibody, or antigen-binding fragments thereof may bind to the same epitope as one of the antibodies, or antigen-binding fragments thereof, described herein, or to an overlapping epitope.
  • Antibodies, or antigen-binding fragments thereof are expected to show similar functional properties (e.g., one or more of the activities described above).
  • the exemplified antibody, or antigen-binding fragment thereof include those described above, including those with: 1) the heavy and/or light chains, 2) VHs and/or VLs, and/or 3) that comprise one or more of the CDRs included in Tables D1 and D2.
  • the antibody, or antigen-binding fragment thereof, that are provided include those that compete with an antibody having: (a) all 6 of the CDRs listed for the antibody described in Table D1; (b) a VH and a VL listed for the antibody described in Table D2; or (c) the light chain and heavy chain as specified for the antibody described in Table D2.
  • competition or cross-competition is determined by surface plasmon resonance analysis (e.g., BIACORE®) (see, e.g., Abdiche, et al., 2009, Anal. Biochem. 386:172-180; Abdiche, et al., 2012, J.
  • Ligand-Drug Conjugate Mixtures and Compositions [0702]
  • the present invention provides Ligand-Drug Conjugate mixtures and pharmaceutical compositions comprising any of the Ligand-Drug Conjugates described herein.
  • the mixtures and pharmaceutical compositions comprise a plurality of conjugates.
  • each of the conjugates in the mixture or composition is identical or substantially identical, however, the distribution of drug-linkers on the ligands in the mixture or compositions may vary as well as the drug loading.
  • the conjugation technology used to conjugate drug-linkers to antibodies as the targeting agent results in a composition or mixture that is heterogeneous with respect to the distribution of Drug-Linker compounds on the antibody (Ligand Unit) within the mixture and/or composition.
  • the loading of Drug-Linker compounds on each of the antibody molecules in a mixture or composition of such molecules is an integer that ranges from 1 to 16.
  • the loading of drug-linkers is a number ranging from 1 to about 16. Within the composition or mixture, there sometimes is a small percentage of unconjugated antibodies.
  • the average number of drug-linkers per Ligand Unit in the mixture or composition is an important attribute as it determines the maximum amount of drug that is delivered to the target cell.
  • the average drug load is 1, 2 or about 2, 3 or about 3, 4 or about 4, 5 or about 5, 6 or about 6, 7 or about 7, 8 or about 8, 9 or about 9, 10 or about 10, 11 or about 11, 12 or about 12, 13 or about 13, 14 or about 14, 15 or about 15, 16 or about 16.
  • the average drug loading is from about 1 to about 16, from about 2 to about 12, from about 3 to about 8, or about 4.
  • the average drug loading is from about 3 to about 5, from about 3.5 to about 4.5, from about 3.7 to about 4.3, from about 3.9 to about 4.3, or about 4.
  • the mixtures and pharmaceutical compositions comprise a plurality (i.e., population) of conjugates, however, the conjugates are identical or substantially identical and are substantially homogenous with respect to the distribution of drug-linkers on the ligand molecules within the mixture and/or composition and with respect to loading of drug-linkers on the ligand molecules within the mixture and/or composition.
  • the loading of drug-linkers on an antibody Ligand Unit is 2 or 4. Within the composition or mixture, there may also be a small percentage of unconjugated antibodies.
  • the average drug load in such embodiments is about 2 or about 4.
  • such compositions and mixtures result from the use of site-specific conjugation techniques and conjugation is due to an introduced cysteine residue.
  • the average number of Drug Units or Drug-Linker compounds per Ligand Unit in a preparation from a conjugation reaction may be characterized by conventional means such as mass spectrometry, ELISA assay, HPLC (e.g., HIC).
  • HPLC e.g., HIC
  • the quantitative distribution of Ligand-Drug Conjugates in terms of subscript p may also be determined.
  • separation, purification, and characterization of homogeneous Ligand-Drug Conjugates may be achieved by conventional means such as reverse phase HPLC or electrophoresis.
  • the compositions are pharmaceutical compositions comprising the Ligand-Drug Conjugates described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is in liquid form.
  • the pharmaceutical composition is a solid.
  • the pharmaceutical composition is a lyophilized powder.
  • the compositions, including pharmaceutical compositions are provided in purified form. As used herein, “purified” means that when isolated, the isolate contains at least 95%, and in other embodiments at least 98%, of Conjugate by weight of the isolate.
  • the Ligand-Drug Conjugates are useful for inhibiting the multiplication of a tumor cell or cancer cell, causing apoptosis in a tumor or cancer cell, or for treating a cancer in a patient.
  • the Ligand-Drug Conjugates are used accordingly in a variety of settings for the treatment of cancers.
  • the Ligand-Drug Conjugates are intended to deliver a drug to a tumor cell or cancer cell.
  • the Ligand Unit of a Ligand-Drug Conjugate binds to or associates with a cancer-cell or a tumor-cell-associated antigen, and the Ligand-Drug Conjugate is taken up (internalized) inside the tumor cell or cancer cell through receptor-mediated endocytosis or other internalization mechanism.
  • the antigen is attached to a tumor cell or cancer cell or is an extracellular matrix protein associated with the tumor cell or cancer cell. Once inside the cell, via activation of the Activation Unit, the drug is released within the cell.
  • the free drug is released from the Ligand-Drug Conjugate outside the tumor cell or cancer cell, and the free drug subsequently penetrates the cell.
  • the Ligand Unit binds to the tumor cell or cancer cell.
  • the Ligand Unit binds to a tumor cell or cancer cell antigen which is on the surface of the tumor cell or cancer cell.
  • the Ligand Unit binds to a tumor cell or cancer cell antigen that is an extracellular matrix protein associated with the tumor cell or cancer cell.
  • the specificity of the Ligand Unit for a particular tumor cell or cancer cell is an important consideration for determining the tumors or cancers that are most effectively treated.
  • Ligand-Drug Conjugates that target a cancer cell antigen present on hematopoietic cancers are useful treating hematologic malignancies (e.g., anti-CD30, anti- CD70, anti-CD19, anti-CD33 binding Ligand Unit (e.g., antibody) are useful for treating hematologic malignancies).
  • Ligand-Drug Conjugates that target a cancer cell antigen present on solid tumors in some embodiments are useful treating such solid tumors.
  • Cancers that are intended to be treated with a Drug-Linker Conjugate include, but are not limited to, hematopoietic cancers such as, for example, lymphomas (Hodgkin Lymphoma and Non-Hodgkin Lymphomas) and leukemias and solid tumors.
  • hematopoietic cancers include, follicular lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, acute myeloblastic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, diffuse large B cell lymphoma, and multiple myeloma.
  • solid tumors include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hep
  • the treated cancer is any one of the above-listed lymphomas and leukemias.
  • Multi-Modality Therapy for Cancer Cancers, including, but not limited to, a tumor, metastasis, or other disease or disorder characterized by uncontrolled cell growth are intended to be treated or inhibited by administration of an effective amount of a Ligand-Drug Conjugate.
  • methods for treating cancer including administering to a patient in need thereof an effective amount of a Ligand-Drug Conjugate and a chemotherapeutic agent.
  • the chemotherapeutic agent is one in which treatment of the cancer has not been found to be refractory to that agent.
  • the chemotherapeutic agent one in which the treatment of cancer has been found to be refractory to that agent.
  • the Ligand-Drug Conjugates is administered to a patient that has also undergone surgery as treatment for the cancer.
  • a chemotherapeutic agent is typically administered over a series of sessions, or one or a combination of the chemotherapeutic agents, such a standard of care chemotherapeutic agent(s), is administered.
  • the patient also receives an additional treatment, such as radiation therapy.
  • the Ligand-Drug Conjugate is administered concurrently with the chemotherapeutic agent or with radiation therapy.
  • the chemotherapeutic agent or radiation therapy is administered prior or subsequent to administration of a Ligand-Drug Conjugate.
  • methods of treatment of cancer with a Ligand-Drug Conjugate are provided as an alternative to chemotherapy or radiation therapy where the chemotherapy or the radiation therapy has proven or can prove too toxic, e.g., results in unacceptable or unbearable side effects, for the subject being treated.
  • the patient being treated is optionally treated with another cancer treatment such as surgery, radiation therapy or chemotherapy, depending on which treatment is found to be acceptable or bearable.
  • Treatment of Autoimmune Diseases [0720]
  • the Ligand-Drug Conjugates are intended to be useful for killing or inhibiting the unwanted replication of cells that produce an autoimmune disease or for treating an autoimmune disease.
  • the Ligand-Drug Conjugates are used accordingly in a variety of settings for the treatment of an autoimmune disease in a patient.
  • the Ligand-Drug Conjugates are typically used to deliver a Drug Unit to a target cell.
  • the Ligand-Drug Conjugate associates with an antigen on the surface of a pro- inflammatory or inappropriately stimulated immune cell, and the Ligand-Drug Conjugate is then taken up inside the targeted cell through receptor-mediated endocytosis. Once inside the cell, the Linker Unit is cleaved, resulting in release of the Drug Unit as free drug. The free drug is then able to migrate within the cytosol and induce a cytotoxic or cytostatic activity.
  • the Drug Unit is cleaved from the Ligand-Drug Conjugate outside the target cell, and the free drug resulting from that release subsequently penetrates the cell.
  • the Ligand Unit binds to an autoimmune antigen.
  • the antigen is on the surface of a cell involved in an autoimmune condition.
  • the Ligand Unit binds to activated lymphocytes that are associated with the autoimmune disease state.
  • the Ligand-Drug Conjugate kills or inhibits the multiplication of cells that produce an autoimmune antibody associated with a particular autoimmune disease.

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Abstract

Hydrophilic auristatin compounds are described, including Drug-Linker compounds, Ligand-Drug Conjugate compounds, methods of use, and preparations thereof.

Description

CYTOTOXIC COMPOUNDS AND CONJUGATES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS [0001] This patent application claims the priority benefit of U.S. Provisional Application No. 63/397,776, filed on August 12, 2022, and EP Application No. 22202077.8, filed on October 18, 2022, the contents of each of which are incorporated herein by reference in their entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0002] The contents of the electronic sequence listing (761682007641SEQLIST.xml; Size: 966,947 bytes; and Date of Creation: August 10, 2023) are herein incorporated by reference in their entirety. BACKGROUND OF THE INVENTION [0003] A variety of ligands have been investigated for the targeted delivery of cytotoxic agents to tumor cells, including oligopeptides, antibodies, and other proteins. While various drug classes have been evaluated for targeted delivery by these ligands, only a few drug classes have proved sufficiently active as Ligand-Drug Conjugates, while having a suitable toxicity profile and other pharmacological properties, to warrant clinical development. There is thus a need for additional cytotoxic agents with improved toxicity profile and other pharmacological properties. [0004] The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 4th edition (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor N.Y.; Current Protocols In Molecular Biology (F. M. Ausubel, et al. eds., (2003)); the series METHODS IN ENZYMOLOGY (Academic Press, Inc.); PCR 2: A Practical Approach (M. J. MacPherson, B. D. Hames and G. R. Taylor eds. (1995)); Greenfield, ed. (2013) Antibodies, A Laboratory Manual, 2nd edition, Cold Spring Harbor Laboratory Press; Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R. I. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Roberts, 1998) Plenum Press; Cell and Tissue Culture Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D. M. Weir and C. C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J. M. Miller and M. P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J. E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995); Cancer: Principles and Practice of Oncology (V. T. DeVita et al., eds., J.B. Lippincott Company, 1993); and updated versions thereof. Each of the foregoing references in this paragraph is incorporated herein by reference in its entirety. BRIEF SUMMARY OF THE INVENTION [0005] Provided herein is a compound of Formula (I):
Figure imgf000004_0001
or a salt thereof, wherein Xb is -NR1R2; and Xa is
Figure imgf000004_0002
Xa and Xb are taken together with the carbon atom to which they are attached to form wherein the asterisk denotes the ca a
Figure imgf000004_0003
rbon atom of Formula (I) that bears the X and Xb groups; R1, R2, R3, R4, Ra, Rb, R5, and R10 are each independently H or C1-C4 alkyl; X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; and q is 0 or 1, wherein when X is H, at least two of R7, R8, R9, and R11 comprise an OH moiety. [0006] Also provided herein is a compound of Formula (II):
Figure imgf000005_0001
or a salt thereof, wherein R1, R3, and R4 are independently H or C1-C4 alkyl; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, or 2; and q is 0 or 1. [0007] In some embodiments of Formula (I) and (II), q is 0. In some embodiments, q is 1. In some embodiments, R11 is H. In some embodiments, R11 is OH. [0008] In some embodiments of Formula (I), X is OH. In some embodiments, X is -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, Xb is -NR1R2 and Xa is
Figure imgf000005_0002
. In some embodiments, R3 is H. In some embodiments, R4 is H. In some embodiments, n is 0 or 1. In some embodiments, Xa and Xb are taken together with
Figure imgf000006_0001
the carbon atom to which they are attached to form , wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups. In some embodiments, m is 2 or 3. [0009] In some embodiments of Formula (I) or (II), R1 is H. In some embodiments, R1 is C1-C4 alkyl. In some embodiments, R1 is methyl. In some embodiments, R2 is methyl. In some embodiments, R10 is H. In some embodiments, R10 is methyl. In some embodiments, R6 is unsubstituted C1-C4 alkyl. In some embodiments, R6 is isopropyl. In some embodiments, R6 is C1-C4 alkyl substituted with OH. In some embodiments, R7 C1-C4 alkyl substituted with OH. In some embodiments, R7 is -CH2OH. In some embodiments, R7 is H. In some embodiments, R7 is unsubstituted C1-C4 alkyl. In some embodiments, R7 is methyl. In some embodiments, R7 is 5-6 membered heteroaryl. In some embodiments, R8 is H. In some embodiments, R8 is OH. In some embodiments, E is phenyl. In some embodiments, E-R9 is
Figure imgf000006_0002
, wherein the wavy line indicates the point of attachment of E to the rest of the compound. In some embodiments, E is 5-6 membered heteroaryl. In some embodiments, R9 is H. In some embodiments, R9 is OH. [0010] In some embodiments of Formula (I),
Figure imgf000006_0003
Xb is -NR1R2; R1 is H or methyl; R2 is methyl; X is OH; R3 and R4 are H; R6 is isopropyl; R7 is -CH2OH; R8 is H; E is phenyl; and R9 is H. [0011] In some embodiments of Formula (I), the compound is
Figure imgf000007_0001
or a salt thereof. [0012] In some embodiments, the compound is a compound of Table 1. [0013] Also provided herein is a Drug-Linker compound of the following formula: Q-D, or a salt thereof, wherein Q is a Linker Unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S*-RL-, (iv) Z'-A-S*-RL-Y-, (v) Z'-A-B(S*)-RL-, (vi) Z'-A-B(S*)-RL-Y-, (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-; Z' is a Stretcher Unit precursor; A is a bond or a Connector Unit; B is a Parallel Connector Unit; S* is a Partitioning Agent; RL is a Releasable Linker; W is an Amino Acid Unit; Y is a Spacer Unit; and D is a Drug Unit of Formula (I'):
Figure imgf000007_0002
wherein Xb is -NR2-# or -N+R1R5-#, wherein the # denotes the point of attachment to Q, and Xa
Figure imgf000008_0001
Xa and Xb are taken together with the carbon atom to which they are attached to form
Figure imgf000008_0002
wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups, and the # denotes the point of attachment to Q; R1 and R5 are independently C1-C4 alkyl; X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R2, R3, R4, R10, Ra, and Rb are each independently H or C1-C4 alkyl; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1; and wherein when X is H, at least two of R7, R8, R9, and R11 comprise an OH moiety. [0014] In some embodiments, the Linker Unit Q is of formula (i), (ii), (iii), (iv), (x), or (xi). In some embodiments, the Linker Unit Q is of formula (v), (vi), (ix), or (xi). In some embodiments, the Linker Unit Q is of formula (viii), (ix), (x), or (xi). [0015] In some embodimemts, the Stretcher Unit Z' is
Figure imgf000008_0003
wherein R17 is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O-(C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3-C8 heterocyclo-, -C1-C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene- , -C1-C10 alkylene-C(=O)-, C1-C10 heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O- (C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8 heterocyclo)-C(=O)-, - (C3-C8 heterocyclo)-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-NH-, C1-C10 heteroalkylene- NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene- arylene-NH-, -arylene-C1-C10 alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, -(C3- C8 carbocyclo)-C1-C10 alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, -C3-C8 carbocyclo-S -, -O-(C1-C8 alkylene)-S -, -arylene-S-, -C1-C10 alkylene-arylene-S-, -arylene-C1-C10 alkylene-S-, -C1-C10 alkylene-(C3-C8 carbocyclo)-S-, - (C3-C8 carbocyclo)-C1-C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-; subscript k is an integer ranging from 1 to 36; R17 is optionally substituted by a Basic Unit (BU) such as an aminoalkyl moiety, e.g. –(CH2 )xNH2, –(CH2 )xNHRa, and –(CH2 )xNRa 2, wherein x is an integer of from 1-4 and each Ra is independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or two Ra groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group; and the wavy line indicates the point of covalent attachment to the rest of the Drug-Linker compound. [0016] In some embodiments, the Stretcher Unit Z' is
Figure imgf000010_0001
wherein the wavy lines indicate the point of covalent attachment to the rest of the Drug-Linker compound. [0017] In some embodiments, the Connector Unit A is
Figure imgf000010_0002
wherein each R100 is independently selected from hydrogen or -C1-C3 alkyl; R111 is independently selected from the group consisting of hydrogen, p- hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, - CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, - (CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, - (CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, - (CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3- pyridylmethyl-, 4-pyridylmethyl-,
Figure imgf000011_0001
each subscript c is an independently selected integer from 1 to 10; and the wavy lines indicate attachment of the Connector Unit to the rest of the Drug- Linker compound. [0018] In some embodiments, the Connector Unit A is
Figure imgf000011_0002
c is an integer ranging from 1 to 6; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof. [0019] In some embodiments, A is a bond. [0020] In some embodiments,
Figure imgf000011_0003
each AA is independently a proteinogenic or non-proteinogenic amino acid; and the wavy lines indicate points of attachment to the rest of the Drug-Linker compound or salt thereof. [0021] In some embodiments, B is an amino acid. In some embodiments, B is
Figure imgf000012_0001
the wavy line indicates the point of attachement to the Partitioning Agent S*; and the asterisks indicate points of attachment to the rest of the Drug-Linker structure. [0022] In some embodiments, the Partitioning Agent S* is a polyethylene glycol (PEG) unit, cyclodextrin unit, polyamide, hydrophilic peptide, polysaccharide, or dendrimer. In some embodiments, Partitioning Agent S* is a PEG Unit comprising from 4 to 72 (CH2CH2O) subunits. In some embodiments, the PEG Unit is
Figure imgf000012_0002
; b is selected from the group consisting of 4 to 36; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof. [0023] In some embodiments, the Releasable Linker RL is –(AA)1-12–; and each AA is independently a proteinogenic or non-proteinogenic amino acid. [0024] In some embodiments, the Releasable Linker RL is –AA1-AA2– or –AA1-AA2-AA3–, wherein AA1 is attached to the Stretcher Unit Z' or the Connector Unit A. In some embodiments, the Releasable Linker RL is
Figure imgf000013_0001
the wavy line adjacent to the -NH- group indicates attachment to the Stretcher Unit Z' or the Connector Unit A and the wavy line adjacent to the -C(=O)- group indicates attachment to the Spacer Unit Y or the Drug Unit D. [0025] In some embodiments, the Releasable Linker RL is a glycoside. In some embodiments, the Releasable Linker RL is
Figure imgf000013_0002
wherein Su is a hexose form a monosaccharide; O' represents the oxygen atom of a glycosidic bond that is capable of cleavage by a glycosidase; the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q. [0026] In some embodiments, the Releasable Linker RL is
Figure imgf000014_0001
the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q. [0027] In some embodiments, the Spacer Unit Y is
Figure imgf000014_0002
wherein EWG is an electron-withdrawing group; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof. [0028] In some embodiments, the Spacer Unit Y is
Figure imgf000014_0003
the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof. [0029] In some embodiments, Z' is
Figure imgf000014_0004
R17 is C1-C10 alkylene; A is a bond; RL is –AA1-AA2–; AA1 and AA2 are each independently a proteinogenic amino acid;
Figure imgf000015_0001
and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof. [0030] In some embodiments, Z' is
Figure imgf000015_0002
A is a bond; RL is
Figure imgf000015_0003
and Y is
Figure imgf000015_0004
[0031] In some embodiments, Y-D is and
Figure imgf000015_0005
the wavy line indicates the site of attachment to the rest of the Drug-Linker compound or salt thereof. [0032] In some embodiments, Y-D is
Figure imgf000016_0001
and the wavy line indicates the site of attachment to the rest of the Drug-Linker compound or salt thereof. [0033] In some embodiments, the compound is
Figure imgf000016_0002
or a salt thereof. [0034] In some embodiments, the compound is
Figure imgf000016_0003
or
Figure imgf000016_0004
or a salt thereof. [0035] In some embodiments, the Drug-Linker compound is a compound of Table 2. [0036] Also provided herein is a Ligand-Drug Conjugate compound of the formula: L-(Q-D)p or a pharmaceutically acceptable salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S*-RL-, (iv) Z'-A-S*-RL-Y-, (v) Z'-A-B(S*)-RL-, (vi) Z'-A-B(S*)-RL-Y-, (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-; Z' is a Stretcher Unit precursor; A is a bond or a Connector Unit; B is a Parallel Connector Unit; S* is a Partitioning Agent; RL is a Releasable Linker; W is a Amino Acid Unit; Y is a Spacer Unit; and D is a Drug Unit of Formula (I'):
Figure imgf000017_0001
wherein Xb is -NR2-# or -N+R1R5-#, wherein the # denotes the point of attachment to Q, and Xa
Figure imgf000018_0002
Xa and Xb are taken together with the carbon atom to which they are attached to form
Figure imgf000018_0003
, wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups, and the # denotes the point of attachment to Q; R1 and R5 are independently C1-C4 alkyl; X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R2, R3, R4, R10, Ra, and Rb are each independently H or C1-C4 alkyl; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1; and wherein when X is H, at least two of R7, R8, R9, and R11 comprise an OH moiety. [0037] In some embodiments, the Linker Unit Q is of formula (i), (ii), (iii), (iv), (x), or (xi). In some embodiments, the Linker Unit Q is of formula (v), (vi), (ix), or (xi). In some embodiments, the Linker Unit Q is of formula (viii), (ix), (x), or (xi). [0038] In some embodiments, the Ligand Unit L and the Stretcher Unit Z together are
Figure imgf000018_0001
Figure imgf000019_0001
, wherein R17 is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O-(C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3- C8 heterocyclo-, -C1-C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene- , -C1-C10 alkylene-C(=O)-, C1-C10 heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O- (C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8 heterocyclo)-C(=O)-, - (C3-C8 heterocyclo)-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-NH-, C1-C10 heteroalkylene- NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene- arylene-NH-, -arylene-C1-C10 alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, -(C3- C8 carbocyclo)-C1-C10 alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, -C3-C8 carbocyclo-S -, -O-(C1-C8 alkylene)-S -, -arylene-S-, -C1-C10 alkylene-arylene-S-, -arylene-C1-C10 alkylene-S-, -C1-C10 alkylene-(C3-C8 carbocyclo)-S-, - (C3-C8 carbocyclo)-C1-C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-; subscript k is an integer ranging from 1 to 36; R17 is optionally substituted by a Basic Unit (BU) such as an aminoalkyl moiety, e.g. –(CH2 )xNH2, –(CH2 )xNHRa, and –(CH2 )xNRa 2, wherein x is an integer of from 1-4 and each Ra is independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or two Ra groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group; and the wavy line indicates the point of covalent attachment to the rest of the Ligand-Drug Conjugate compound. [0039] In some embodiments, the Ligand Unit L and the Stretcher Unit Z together are
Figure imgf000020_0001
Figure imgf000021_0001
wherein the wavy lines indicate the point of covalent attachment to the rest of the Ligand-Drug Conjugate compound. [0040] In some embodiments, the Connector Unit A is
Figure imgf000022_0001
wherein each R100 is independently selected from hydrogen or -C1-C3 alkyl; R111 is independently selected from the group consisting of hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-,
Figure imgf000022_0002
each subscript c is an independently selected integer from 1 to 10; and the wavy lines indicate attachment of the Connector Unit to the rest of the Ligand- Drug Conjugate compound or pharmaceutically acceptable salt thereof. [0041] In some embodiments, the Connector Unit A is
Figure imgf000022_0003
c is an integer ranging from 1 to 6; and the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof. [0042] In some embodiments, A is a bond. [0043] In some embodiments,
Figure imgf000023_0001
each AA is independently a proteinogenic or non-proteinogenic amino acid; and the wavy lines indicate points of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof. [0044] In some embodiments, B is an amino acid. In some embodiments, B is
Figure imgf000023_0002
the wavy line indicates the point of attachement to the Partitioning Agent S*; and the asterisks indicate points of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof. [0045] In some embodiments, the Partitioning Agent S* is a polyethylene glycol (PEG) unit, cyclodextrin unit, polyamide, hydrophilic peptide, polysaccharide, or dendrimer. In some embodiments, the Partitioning Agent S* is a PEG Unit comprising from 4 to 72 (CH2CH2O) subunits. In some embodiments, the PEG Unit is
Figure imgf000024_0001
; b is selected from the group consisting of 4 to 36; and the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof. [0046] In some embodiments, the Releasable Linker RL is –(AA)1-12–; and each AA is independently a proteinogenic or non-proteinogenic amino acid. [0047] In some embodiments, the Releasable Linker RL is –AA1-AA2– or –AA1-AA2-AA3–, wherein AA1 is attached to the Stretcher Unit Z or the Connector Unit A. [0048] In some embodiments, the Releasable Linker RL is
Figure imgf000024_0002
the wavy line adjacent to the -NH- group indicates attachment to the Stretcher Unit Z or the Connector Unit A and the wavy line adjacent to the -C(=O)- group indicates attachment to the Spacer Unit Y or the Drug Unit D. [0049] In some embodiments, the Releasable Linker RL is a glycoside. [0050] In some embodiments, the Releasable Linker RL is
Figure imgf000025_0001
wherein Su is a hexose form a monosaccharide; O' represents the oxygen atom of a glycosidic bond that is capable of cleavage by a glycosidase; the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q. [0051] In some embodiments, the Releasable Linker RL is
Figure imgf000025_0002
the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q. [0052] In some embodiments, the Spacer Unit Y is
Figure imgf000025_0003
wherein EWG is an electron-withdrawing group; and the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof. [0053] In some embodiments, the Spacer Unit Y is
Figure imgf000026_0001
the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof. [0054] In some embodiments, R17 is C1-C10 alkylene; A is a bond; RL is –AA1-AA2–; AA1 and AA2 are each independently a proteinogenic amino acid;
Figure imgf000026_0002
the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof. [0055] In some embodiments, A is a bond;
Figure imgf000026_0003
. [0056] In some embodiments, Y-D is
Figure imgf000027_0001
the wavy line indicates the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof. [0057] In some embodiments, Y-D is
Figure imgf000027_0002
the wavy line indicates the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof. [0058] In some embodiments, the compound is
Figure imgf000027_0003
,
Figure imgf000028_0001
Figure imgf000029_0001
or a pharmaceutically acceptable salt thereof. [0059] In some embodiments, the Ligand-Drug Conjugate compound is a compound of Table 3. [0060] In some embodiments, p is an integer ranging from 2 to 6. In some embodiments, p is 4. [0061] Also provided herein is a pharmaceutical composition comprising a Ligand-Drug Conjguate compound as described herein and a pharmaceutically acceptable excipient. In some embodiments, the composition comprises a plurlaity of Ligand-Drug Conjugate compounds with an average drug loading from 2 to 8. In some embodiments, the average drug loading is about 4. In some embodiments, the average drug loading is from 3.5 to 4.5. [0062] Also provided herein is a method of treating cancer comprising administering a therapeutically effective amount of the Ligand-Drug Conjugate compound of any one of claims 66-96, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the subject tolerates treatment with the Ligand-Drug Conjugate compound better than treatment with another Ligand-Drug Conjugate compound in therapeutically effective doses. In some embodiments, the another Ligand-Drug Conjugate compound comprises a monomethyl auristatin E or monomethyl auristatin F Drug Unit. BRIEF DISCRIPTION OF THE FIGURES [0063] FIG 1. Illustrates the in vivo mean tumor volume data for various Ag1 ADCs in the A2058 melanoma xenograft model. [0064] FIG 2. Illustrates the in vivo mean tumor volume data for various h2A2 ADCs in the Detroit562 pharyngeal cancer xenograft model. [0065] FIG 3. Illustrates the in vivo median tumor volume data for various cAC10 ADCs in the Karpas/KarpasBVR admixed Hodgkin lymphoma xenograft model. [0066] FIG 4. Illustrates the in vivo mean tumor volume data for various cAC10 ADCs in the Karpas Hodgkin lymphoma xenograft model. [0067] FIG 5. Illustrates the in vivo mean tumor volume data for various cAC10 ADCs in the Karpas Hodgkin lymphoma xenograft model. [0068] FIG 6. Summarizes plasma neutrophil levels at day 5 and day 8 following administration by non-binding ADCs to rats. [0069] FIG 7. Summarizes reticulocyte levels at day 5 and day 8 following administration by non-binding ADCs to rats. [0070] FIG 8. Summarizes platelet levels at day 5 and day 8 following administration by non-binding ADCs to rats. [0071] FIG 9. Summarizes aspartate transaminase (AST) levels at day 8 following administration by non-binding ADCs to rats. [0072] FIG 10. Illustrates the efficacy of a variety of hCR011 ADCs and a non-binding control ADC as measured in the WM2664 melanoma xenograft model. [0073] FIG 11. Illustrates the efficacy of a variety of hCR011 ADCs and non-binding control ADCs as measured in the SKMEL5 melanoma xenograft model. [0074] FIG 12. Illustrates the efficacy of non-binding, Ag2, and hCR011 ADCs as measured in the PDX_1 melanoma xenograft model. [0075] FIG 13. Illustrates the efficacy of non-binding, Ag2 and hCR011 ADCs as measured in the PDX_4 melanoma xenograft model. [0076] FIG 14. Illustrates the efficacy of non-binding, Ag2 and hCR011 ADCs as measured in the PDX_3 NSCLC xenograft model. [0077] FIG 15. Illustrates the efficacy of non-binding, Ag2 and hCR011 ADCs as measured in the PDX_2 NSCLC xenograft model. [0078] FIG 16. Summarizes the anti-tumor activity of 6 hCR011 ADCs using AUC.3. [0079] FIG 17. Summarizes plasma neutrophil levels at baseline, day 4, day 15, and day 29 following administration of hCR011 ADCs to cynomologous monkeys. [0080] FIG 18. Summarizes reticulocyte levels at baseline, day 4, day 15, and day 29 following administration of hCR011 ADCs to cynomologous monkeys. [0081] FIG 19. Summarizes platelet levels at baseline, day 4, day 15, and day 29 following administration of hCR011 ADCs to cynomologous monkeys. [0082] FIG 20. Summarizes aspartate transaminase levels at baseline and day 8 following administration of hCR011 ADCs to cynomologous monkeys. [0083] FIG 21. shows neutrophil counts from blood samples taken prior to dosing and post-dose on Day 8. DETAILED DESCRIPTION OF THE INVENTION [0084] One drug class of interest for use in Ligand-Drug Conjguates is auristatins. Auristatins have been shown to be effective payloads in some Ligand-Drug Conjugates (LDCs), but it is believed that their hydrophobicity can contribute to off-target toxicity due to increased permeability and high bystander activity of the free auristatin. Additionally, hydrophobic payloads, such as auristatins, may increase the hydrophobicity of the LDC, resulting in rapid clearance of the LDC from the body of a subject. Therefore, there is a need for auristain conjugates engineered to have optimized cell permeability, pharmacokinetics, and toxicity profile. [0085] Without being bound by theory, it is believed that the hydrophilic groups of the auristatin compounds provided herein influence the properties of the compounds and of resulting conjugates (e.g., Ligand-Drug Conjugates). The hydrophilic groups are believed to increase the effectiveness of the resulting conjugates in two ways. Conjugates comprising a hydrophilic auristatin group may improve tumor exposure to the Drug Unit due to decreased plasma clearance, and they may simultaneously demonstrate reduced off-target toxicity due to decreased cell permeability of the free drug after it is released from the conjugate. I. Definitions [0086] Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings. When trade names are used herein, the trade name includes the product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context. [0087] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 5th ed., 2013, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, 2nd ed., 2006, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure. [0088] Unless otherwise required by context or expressly indicated, singular terms shall include pluralities and plural terms shall include the singular. [0089] It is understood that aspect and embodiments of the invention described herein include “comprising,” “consisting,” and/or “consisting essentially of” aspects and embodiments. [0090] As used herein, the singular form “a”, “an”, and “the” should be understood to refer to “one or more” of any recited or enumerated component unless indicated otherwise. [0091] The term "about" refers to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. As is understood by one skilled in the art, reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X”. [0092] As described herein, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated. [0093] When a trade name is used herein, reference to the trade name also refers to the product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context. [0094] The term "and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and/or" as used in a phrase such as "A and/or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and/or" as used in a phrase such as "A, B, and/or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). [0095] The term “antibody” as used herein is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (i.e., antigen- binding fragments) that retain, at least in part, one or more of the the desired biological activities of the full-length antibody, for example, affinity for its cognate antigen. The native form of an antibody is a tetramer and consists of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain. In each pair, the light and heavy chain variable regions (VL and VH) are together primarily responsible for binding to an antigen. The light chain and heavy chain variable domains consist of a framework region interrupted by three hypervariable regions, also called “complementarity determining regions” or “CDRs.” In some aspects, the constant regions are recognized by and interact with the immune system (see, e.g., Janeway et al., 2001, Immunol. Biology, 5th Ed., Garland Publishing, New York). The antibodies herein are of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or subclass thereof. In some aspects, the antibody is derived from a suitable species. In some embodiments, the antibody is of human or murine origin. In some aspects, the antibody is human, humanized, or chimeric. An antibody can be human, humanized, chimeric and/or affinity matured, as well as an antibody from other species, for example, mouse and rabbit, etc. The term “antibody” thus includes, for instance, a polypeptide product of B cells within the immunoglobulin class of polypeptides that is able to bind to a specific molecular antigen and is composed of two identical pairs of polypeptide chains, wherein each pair has one heavy chain (about 50-70 kDa) and one light chain (about 25 kDa), each amino-terminal portion of each chain includes a variable region of about 100 to about 130 or more amino acids, and each carboxy-terminal portion of each chain includes a constant region. See, e.g., Antibody Engineering (Borrebaeck ed., 2d ed. 1995); and Kuby, Immunology (3d ed. 1997). The term “antibody” also includes, but is not limited to, synthetic antibodies, recombinantly produced antibodies, camelized antibodies, intrabodies, anti-idiotypic (anti-Id) antibodies, and functional fragments (e.g., antigen-binding fragments) of any of the above, which refers to a portion of an antibody heavy and/or light chain polypeptide that retains some or all of the binding activity of the antibody from which the fragment was derived. Non-limiting examples of functional fragments (e.g., antigen-binding fragments) include single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), Fab fragments, F(ab’) fragments, F(ab)2 fragments, F(ab’)2 fragments, disulfide-linked Fvs (dsFv), Fd fragments, Fv fragments, diabody, triabodies, tetrabodies, and minibodies. In particular, antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, for example, antigen-binding domains or molecules that contain an antigen- binding site that binds to an antigen (e.g., one or more CDRs of an antibody). Such antibody fragments can be found in, for example, Harlow and Lane, Antibodies: A Laboratory Manual (1989); Mol. Biology and Biotechnology: A Comprehensive Desk Reference (Myers ed., 1995); Huston et al., 1993, Cell Biophysics 22:189-224; Plückthun and Skerra, 1989, Meth. Enzymol. 178:497-515; and Day, Advanced Immunochemistry (2d ed. 1990). The antibodies provided herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) of immunoglobulin molecule. [0096] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that are present, in some aspects, in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method. [0097] An “intact antibody” is one which comprises an antigen-binding variable region as well as a light chain constant domain (CL) and heavy chain constant domains, CH1, CH2, CH3, and CH4, as appropriate for the antibody class. In some aspects the constant domains are native sequence constant domains (e.g., human native sequence constant domains) and in other aspects are amino acid sequence variants thereof. [0098] An “antibody fragment” comprises a portion of an intact antibody, comprising the antigen-binding or variable region thereof. Examples of antibody fragments include Fab, Fab’, F(ab’)2, and Fv fragments, diabodies, triabodies, tetrabodies, linear antibodies, single- chain antibody molecules, scFv, scFv-Fc, multispecific antibody fragments formed from antibody fragment(s), a fragment(s) produced by a Fab expression library, or an epitope- binding fragments of any of the above which immunospecifically bind to a target antigen (e.g., a cancer cell antigen, a viral antigen or a microbial antigen). [0099] An “antigen-binding fragment” (or simply “fragment”) or "antigen-binding domain", of an antigen binding protein (e.g., an antibody) as used herein refers to one or more fragments of an antigen binding protein (e.g., an antibody), regardless of how obtained or synthesized, that retain the ability to specifically bind to the antigen bound by the whole antigen binding protein. Examples of antibody fragments include, but are not limited to, Fv; Fab; Fab'; Fab’-SH; F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments. A “Fv” fragment includes a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain. A “Fab” fragment includes, the constant domain of the light chain and the first constant domain (CH1) of the heavy chain, in addition to the heavy and light chain variable domains of the Fv fragment. A “F(ab')2” fragment includes two Fab fragments joined, near the hinge region, by disulfide bonds. [0100] An “antigen” is an entity to which an antibody specifically binds. [0101] The terms “specific binding” and “specifically binds” mean that the antibody or antibody derivative will bind, in a highly selective manner, with its corresponding epitope of a target antigen and not with the multitude of other antigens. Typically, the antibody or antibody derivative binds with an affinity of at least about 1x10-7 M, and preferably 10-8 M to 10-9 M, 10-10 M, 10-11 M, or 10-12 M and binds to the predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen. [0102] The term "inhibits" or "inhibition of" means to reduce by a measurable amount, or to prevent entirely. [0103] The term “therapeutically effective amount” refers to an amount of a conjugate effective to treat a disease or disorder in a mammal. In the case of cancer, the therapeutically effective amount of the conjugate may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more of the symptoms associated with the cancer. In some aspects, the drug inhibits growth and/or kills existing cancer cell. In some aspects, the drug is cytostatic and/or cytotoxic. For cancer therapy, efficacy is measured by commonly available tools. In some aspects, efficacy is measured by assessing the time to disease progression (TTP) and/or determining the response rate (RR). [0104] As used herein, “Percent (%) amino acid sequence identity” and “homology” with respect to a peptide, polypeptide or antigen binding protein (e.g., antibody) sequence are defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGNTM (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. For example, the % sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be phrased as a given amino acid sequence A that has or comprises a certain % sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 times the fraction X/Y where X is the number of amino acid residues scored as identical matches by the sequence in that program's alignment of A and B, and where Y is the total number of amino acid residues in B. Unless specifically stated otherwise, all % amino acid sequence identity values used herein are calculated according to this formula using the ALIGN-2 computer program. It will be appreciated that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % sequence identity of A to B will not equal the % sequence identity of B to A. [0105] The term “substantial” or “substantially” refers to a majority, i.e. >50% of a population, of a mixture or a sample, preferably more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, or 99% of a population. [0106] The term “cytotoxic activity” refers to a cell-killing effect of a drug or Ligand- Drug Conjugate compound or an intracellular metabolite of a Ligand-Drug Conjugate compound. In some aspects, cytotoxic activity is expressed as the IC50 value, which is the concentration (molar or mass) per unit volume at which half the cells survive. [0107] The term “cytostatic activity” refers to an anti-proliferative effect of a drug or Ligand-Drug Conjugate compound or an intracellular metabolite of a Ligand-Drug Conjugate compound. [0108] The term “cytotoxic agent” as used herein refers to a substance that has cytotoxic activity and causes destruction of cells. The term is intended to include chemotherapeutic agents, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including synthetic analogs and derivatives thereof. [0109] The term “cytostatic agent” as used herein refers to a substance that inhibits a function of cells, including cell growth or multiplication. Cytostatic agents include inhibitors such as protein inhibitors, e.g., enzyme inhibitors. Cytostatic agents have cytostatic activity. [0110] The terms “cancer” and “cancerous” refer to or describe the physiological condition or disorder in mammals that is typically characterized by unregulated cell growth. A “tumor” comprises one or more cancerous cells. [0111] The term "immunoglobulin" refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light (L) low molecular weight chains and one pair of heavy (H) chains, all four inter-connected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, for instance, Fundamental Immunology (Paul, W., ed., 7th ed. Raven Press, N .Y. (2013)). Briefly, each heavy chain typically is comprised of a heavy chain variable region (abbreviated herein as VH or VH) and a heavy chain constant region (CH or CH). The heavy chain constant region typically is comprised of three domains, CH1, CH2, and CH3. The heavy chains are generally inter- connected via disulfide bonds in the so-called “hinge region.” Each light chain typically is comprised of a light chain variable region (abbreviated herein as VL or VL) and a light chain constant region (CL or CL). The light chain constant region typically is comprised of one domain, CL. The CL can be of κ (kappa) or λ (lambda) isotype. The terms “constant domain” and “constant region” are used interchangeably herein. An immunoglobulin can derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those in the art and include but are not limited to human IgG1, IgG2, IgG3 and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgG1) that is encoded by the heavy chain constant region genes. [0112] The term “hypervariable region” or “HVR,” as used herein, refers to each of the regions of an antibody variable domain which are hypervariable in sequence. HVRs can form structurally defined loops (“hypervariable loops”). Generally, native four-chain antibodies comprise six HVRs; three in the VH (H1, H2, H3), and three in the VL (L1, L2, L3). In native antibodies, H3 and L3 display the most diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu, in Methods in Molecular Biology 248:1 -25 (Lo, ed., Human Press, Totowa, NJ, 2003). Indeed, naturally-occurring camelid antibodies consisting of a heavy chain only are functional and stable in the absence of light chain. See, e.g., Hamers-Casterman et al., Nature 363:446-448 (1993); Sheriff et al., Nature Struct. Biol. 3:733-736 (1996). [0113] HVRs generally comprise amino acid residues from the hypervariable loops and/or from the “complementary determining regions” (CDRs), CDRs being of highest sequence variability and/or involved in antigen recognition. A variety of schemes for defining the boundaries of a given CDR are known in the art. For example, the Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et at., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991 )). Chothia refers instead to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). The AbM CDRs represent a compromise between the Kabat CDRs and Chothia structural loops and are used by Oxford Molecular’s AbM antibody modeling software. The “contact” CDRs are based on an analysis of the available complex crystal structures. Additional details on the foregoing schemes as well as other numbering conventions are provided in the following references: Al-Lazikani et al., (1997) J. Mol. Biol. 273: 927-948 ("Chothia" numbering scheme); MacCallum et al., ( 1996) J. Mol. Biol. 262:732-745 (1996), (Contact" numbering scheme); Lefranc M-P., et al., (2003) Dev. Comp. Immunol. 27:55-77 ("IMGT" numbering scheme); and Honegger A. & Pluckthun A. (2001) J. Mol/ Biol. 309:657-70, (AHo numbering scheme). [0114] In some embodiments, the HVR regions and associated sequences are the same as the CDR regions and associated sequences based upon one of the foregoing numbering conventions. As such, residues for exemplary HVRs and/or CDRs are summarized in the Table D1 below. Table D1: Summary of Different CDR Numbering Schemes.
Figure imgf000039_0001
[0115] In some embodiments, HVRs can comprise extended HVRs as follows: 24-36 or 24-34 (L1 ), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 (H1 ), 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH. The variable domain residues are numbered according to Kabat et at., supra, for each of these definitions. [0116] Unless otherwise specified, the terms "CDR" and "complementary determining region" of a given antibody or region thereof, such as a variable region, as well as individual CDRs (e.g., "CDR-H1, CDR-H2) of the antibody or region thereof, should be understood to encompass the complementary determining region as defined by any of the known schemes described herein above. In some instances, the scheme for identification of a particular CDR or CDRs is specified, such as the CDR as defined by the IMGT, Kabat, AbM, Chothia, or Contact method. In other instances, the particular amino acid sequence of a CDR is given. [0117] Thus, in some embodiments, the antigen binding protein comprises CDRs and/or HVRs as defined by the IMGT system. In other embodiments, the antigen binding protein comprises CDRs or HVRs as defined by the Kabat system. In still other embodiments, the antigen binding protein comprises CDRs or HVRs as defined by the AbM system. In further embodiments, the antigen binding protein comprises CDRs or HVRs as defined by the Chothia system. In yet other embodiments, the antigen binding protein comprises CDRs or HVRs as defined by the IMGT system. [0118] The term “variable region” or “variable domain” refers to the domain of an antigen binding protein (e.g., an antibody) heavy or light chain that is involved in binding the antigen binding protein (e.g., antibody) to antigen. The variable regions or domains of the heavy chain and light chain (VH and VL, respectively) of an antigen binding protein such as an antibody can be further subdivided into regions of hypervariability (or hypervariable regions, which may be hypervariable in sequence and/or form of structurally defined loops), such as hypervariable regions (HVRs) or complementarity-determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). In general, there are three HVRs (HVR-H1, HVR-H2, HVR-H3) or CDRs (CDR-H1, CDR-H2, CDR-H3) in each heavy chain variable region, and three HVRs (HVR-L1, HVR-L2, HVR- L3) or CDRs in (CDR-L1, CDR-L2, CDR-L3) in each light chain variable region. “Framework regions” and “FR” are known in the art to refer to the non-HVR or non-CDR portions of the variable regions of the heavy and light chains. In general, there are four FRs in each full-length heavy chain variable region (FR-H1, FR-H2, FR-H3, and FR-H4), and four FRs in each full-length light chain variable region (FR-L1, FR-L2, FR-L3, and FR-L4). Within each VH and VL, three HVRs or CDRs and four FRs are typically arranged from amino-terminus to carboxy-terminus in the following order: FR1, HVR1, FR2, HVR2, FR3, HVR3, FR4 in the case of HVRs, or FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 in the case of CDRs (See also Chothia and Lesk J. Mot. Biol., 195, 901-917 (1987)). A single VH or VL domain can be sufficient to confer antigen-binding specificity. In addition, antibodies that bind a particular antigen can be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al. J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991). [0119] The term “heavy chain variable region” (VH) as used herein refers to a region comprising heavy chain HVR-H1, FR-H2, HVR-H2, FR-H3, and HVR-H3. For example, a heavy chain variable region may comprise heavy chain CDR-H1, FR-H2, CDR-H2, FR-H3, and CDR-H3. In some embodiments, a heavy chain variable region also comprises at least a portion of an FR-H1 and/or at least a portion of an FR-H4. [0120] The term “heavy chain constant region” as used herein refers to a region comprising at least three heavy chain constant domains, CH1, CH2, and CH3. Nonlimiting exemplary heavy chain constant regions include γ, δ, and α. Nonlimiting exemplary heavy chain constant regions also include ε and μ. Each heavy constant region corresponds to an antibody isotype. For example, an antibody comprising a γ constant region is an IgG antibody, an antibody comprising a δ constant region is an IgD antibody, and an antibody comprising an α constant region is an IgA antibody. Further, an antibody comprising a μ constant region is an IgM antibody, and an antibody comprising an ε constant region is an IgE antibody. Certain isotypes can be further subdivided into subclasses. For example, IgG antibodies include, but are not limited to, IgG1 (comprising a γ1 constant region), IgG2 (comprising a γ2 constant region), IgG3 (comprising a γ3 constant region), and IgG4 (comprising a γ4 constant region) antibodies; IgA antibodies include, but are not limited to, IgA1 (comprising an α1 constant region) and IgA2 (comprising an α2 constant region) antibodies; and IgM antibodies include, but are not limited to, IgM1 and IgM2. [0121] The term “heavy chain” (HC) as used herein refers to a polypeptide comprising at least a heavy chain variable region, with or without a leader sequence. In some embodiments, a heavy chain comprises at least a portion of a heavy chain constant region. The term “full- length heavy chain” as used herein refers to a polypeptide comprising a heavy chain variable region and a heavy chain constant region, with or without a leader sequence. [0122] The term “light chain variable region” (VL) as used herein refers to a region comprising light chain HVR-L1, FR-L2, HVR-L2, FR-L3, and HVR-L3. In some embodiments, the light chain variable region comprises light chain CDR-L1, FR-L2, CDR- L2, FR-L3, and CDR-L3. In some embodiments, a light chain variable region also comprises an FR-L1 and/or an FR-L4. [0123] The term “light chain constant region” as used herein refers to a region comprising a light chain constant domain, CL. Nonlimiting exemplary light chain constant regions include λ and κ. [0124] The term “light chain” (LC) as used herein refers to a polypeptide comprising at least a light chain variable region, with or without a leader sequence. In some embodiments, a light chain comprises at least a portion of a light chain constant region. The term “full-length light chain” as used herein refers to a polypeptide comprising a light chain variable region and a light chain constant region, with or without a leader sequence. [0125] The "EU numbering system" or "EU index" is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991). The "EU index as in Kabat" refers to the residue numbering of the human IgG1 EU antibody. Unless stated otherwise herein, references to residue numbers in the constant domain of antibodies means residue numbering by the EU numbering system. [0126] The term "derivative" refers to a molecule (e.g., an antigen binding protein such as an antibody or fragment thereof) that includes a chemical modification other than an insertion, deletion, or substitution of amino acids (or nucleic acids). In certain embodiments, derivatives comprise covalent modifications, including, but not limited to, chemical bonding with polymers, lipids, or other organic or inorganic moieties. In certain embodiments, a derivative of a particular antigen binding protein can have a greater circulating half-life than an antigen binding protein that is not chemically modified. In certain embodiments, a derivative can have improved targeting capacity for desired cells, tissues, and/or organs. In some embodiments, a derivative of an antigen binding protein is covalently modified to include one or more polymers, including, but not limited to, monomethoxy-polyethylene glycol, dextran, cellulose, or other carbohydrate based polymers, poly-(N-vinyl pyrrolidone)- polyethylene glycol, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, as well as mixtures of such polymers. See, e.g., U.S. Pat. Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192 and 4,179,337. [0127] The term "compete" when used in the context of antigen binding proteins (e.g., antibodies or fragments thereof) that compete for the same epitope means competition between antigen binding proteins as determined by an assay in which the antigen binding protein (e.g., an antibody or fragment thereof) being tested (e.g., a test antibody) prevents or inhibits (partially or completely) specific binding of a reference antigen binding protein (e.g., a reference antibody) to a common antigen (e.g., gpNMB or a fragment thereof). Numerous types of competitive binding assays can be used to determine if one antigen binding protein competes with another, including various label-free biosensor approaches such as surface plasmon resonance (SPR) analysis (see, e.g., Abdiche, et al., 2009, Anal. Biochem. 386:172- 180; Abdiche, et al., 2012, J. Immunol Methods 382:101-116; and Abdiche, et al., 2014 PLoS One 9:e92451. Other assays that can be used include: solid phase direct or indirect radioimmunoassay (RIA), solid phase direct or indirect enzyme immunoassay (EIA), sandwich competition assay (see, e.g., Stahli et al., 1983, Methods in Enzymology 9:242- 253); solid phase direct biotin-avidin EIA (see, e.g., Kirkland et al., 1986, J. Immunol. 137:3614-3619) solid phase direct labeled assay, solid phase direct labeled sandwich assay (see, e.g., Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid phase direct label RIA using I-125 label (see, e.g., Morel et al., 1988, Mol. Immunol. 25:7-15); solid phase direct biotin-avidin EIA (see, e.g., Cheung, et al., 1990, Virology 176:546-552); direct labeled RIA (Moldenhauer et al., 1990, Scand. J. Immunol. 32:77-82). Typically, the test antigen binding protein is present in excess (e.g., at least 2x, 5x, 10x, 20x or 100x). Usually, when a competing antigen binding protein is present in excess, it will inhibit specific binding of a reference antigen binding protein to a common antigen by at least 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100%. In instances in in which each antigen binding protein (e.g., an antibody or fragment thereof) detectably inhibits the binding of the other antigen binding protein with its cognate epitope, whether to the same, greater, or lesser extent, the antigen binding proteins are said to “cross-compete” with each other for binding of their respective epitope(s) or to ”cross-block” one another. Typically, such cross- competition studies are done using the conditions and methods described above for competition studies and the extent of blocking is at least 30%, at least 40%, or at least 50% each way. [0128] An “affinity matured” antibody refers to an antibody with one or more alterations in one or more hypervariable regions (HVRs) compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen. In some examples, an affinity matured antibody refers to an antibody with one or more alterations in one or more complementarity determining regions (CDRs) compared to a parent antibody which does not possess such alterations, such alterations resulting in an improvement in the affinity of the antibody for antigen. [0129] As used herein, the term "specifically binds", “binding” or simply “binds” or other related terms in the context of the binding of an antigen binding protein to its target antigen means that the antigen binding protein exhibits essentially background binding to non- target molecules. An antigen binding protein that specifically binds a target antigen (e.g., gpNMB) may, however, cross-react with the corresponding protein (such as gpNMB) from different species. [0130] The term "KD" (M), as used herein, refers to the dissociation equilibrium constant of a particular antigen binding protein-antigen interaction (e.g., antibody-antigen interaction). Affinity, as used herein, and KD are inversely related, such that higher affinity is intended to refer to lower KD, and lower affinity is intended to refer to higher KD. [0131] An “antibody-drug-conjugate” or simply “ADC” refers to an antibody conjugated to a cytotoxic agent or cytostatic agent. An antibody-drug-conjugate typically binds to the target antigen (e.g., gpNMB) on a cell surface followed by internalization of the antibody- drug-conjugate into the cell where the drug is released. [0132] A “cytotoxic effect” refers to the depletion, elimination and/or killing of a target cell. [0133] A “cytotoxic agent” refers to an agent that has a cytotoxic effect on a cell. [0134] A “cytostatic effect” refers to the inhibition of cell proliferation. [0135] A “cytostatic agent” refers to an agent that has a cytostatic effect on a cell, thereby inhibiting the growth of and/or expansion of a specific subset of cells. Cytostatic agents can be conjugated to an antibody or administered in combination with an antibody. [0136] The term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991. [0137] A “functional Fc region” possesses an “effector function” of a native sequence Fc region. Exemplary “effector functions” include Fc receptor binding; C1q binding; complement dependent cytotoxicity (CDC); antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cellular phagocytosis (ADCP); down regulation of cell surface receptors (e.g. B cell receptor; BCR), etc. Such effector functions generally require the Fc region to be combined with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays. [0138] A “native sequence Fc region” comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include a native sequence human IgG1 Fc region (non-A and A allotypes); native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof. [0139] A “variant Fc region” comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification. [0140] “Fc receptor” or “FcR” describes a receptor that binds to the Fc region of an antibody. In some embodiments, an FcγR is a native human FcR. In some embodiments, an FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcγRI, FcγRII, and FcγRIII subclasses, including allelic variants and alternatively spliced forms of those receptors. FcγRII receptors include FcγRIIA (an “activating receptor”) and FcγRIIB (an “inhibiting receptor”), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor FcγRIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain. (see, e.g., Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed, for example, in Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126:330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term “FcR” herein. The term “Fc receptor” or “FcR” also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus (Guyer et al., J. Immunol. 117:587 (1976) and Kim et al., J. Immunol. 24:249 (1994)) and regulation of homeostasis of immunoglobulins. Methods of measuring binding to FcRn are known (see, e.g., Ghetie and Ward., Immunol. Today 18(12):592-598 (1997); Ghetie et al., Nature Biotechnology, 15(7):637-640 (1997); Hinton et al., J. Biol. Chem. 279(8):6213-6216 (2004); WO 2004/92219 (Hinton et al.). [0141] “Effector functions” refer to biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: Clq binding and complement dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); antibody-dependent cellular phagocytosis (ADCP); down regulation of cell surface receptors (e.g. B cell receptor); and B cell activation. Such functions can be affected by, for example, binding of an Fc effector domain(s) to an Fc receptor on an immune cell with phagocytic or lytic activity or by binding of an Fc effector domain(s) to components of the complement system. Typically, the effect(s) mediated by the Fc-binding cells or complement components result in inhibition and/or depletion of the CD33 targeted cell. Fc regions of antibodies can recruit Fc receptor (FcR)- expressing cells and juxtapose them with antibody-coated target cells. Cells expressing surface FcR for IgGs including FcγRIII (CD16), FcγRII (CD32) and FcγRIII (CD64) can act as effector cells for the destruction of IgG-coated cells. Such effector cells include monocytes, macrophages, natural killer (NK) cells, neutrophils and eosinophils. Engagement of FcγR by IgG activates antibody-dependent cellular cytotoxicity (ADCC) or antibody- dependent cellular phagocytosis (ADCP). ADCC is mediated by CD16+ effector cells through the secretion of membrane pore-forming proteins and proteases, while phagocytosis is mediated by CD32+ and CD64+ effector cells (see, e.g., Fundamental Immunology, 4th ed., Paul ed., Lippincott-Raven, N.Y., 1997, Chapters 3, 17 and 30; Uchida et al., 2004, J. Exp. Med. 199:1659-69; Akewanlop et al., 2001, Cancer Res. 61:4061-65; Watanabe et al., 1999, Breast Cancer Res. Treat. 53:199-207. [0142] “Human effector cells” are leukocytes which express one or more FcRs and perform effector functions. In certain embodiments, the cells express at least FcγRIII and perform ADCC effector function(s). Examples of human leukocytes which mediate ADCC include peripheral blood mononuclear cells (PBMC), natural killer (NK) cells, monocytes, cytotoxic T cells, and neutrophils. The effector cells may be isolated from a native source, e.g., from blood. [0143] “Antibody-dependent cell-mediated cytotoxicity” or “ADCC” refers to a mechanism of cytotoxicity in which the Fc region of antibodies bound to antigen on the cell surface of target cells interact with Fc receptors (FcRs) present on certain cytotoxic effector cells (e.g. NK cells, neutrophils, and macrophages). This interaction enables these cytotoxic effector cells to subsequently kill the target cell with cytotoxins. The primary cells for mediating ADCC, NK cells, express FcγRIII only, whereas monocytes express FcγRI, FcγRII, and FcγRIII. FcR expression on hematopoietic cells is summarized in Table 3 on page 464 of Ravetch and Kinet, Annu. Rev. Immunol 9:457-92 (1991). To assess ADCC activity of a molecule of interest, an in vitro ADCC assay, such as that described in US Pat. Nos. 5,500,362 or 5,821,337 or U.S. Pat. No. 6,737,056 (Presta), can be performed. Useful effector cells for such assays include PBMC and NK cells. ADCC activity of the molecule of interest can also be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Natl. Acad. Sci. (USA) 95:652-656 (1998). Additional polypeptide variants with altered Fc region amino acid sequences (polypeptides with a variant Fc region) and increased or decreased ADCC activity are described, e.g., in U.S. Pat. No. 7,923,538, and U.S. Pat. No. 7,994,290. [0144] “Complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to the Fc region of antibodies (of the appropriate subclass), which are bound to their cognate antigen on a target cell. This binding activates a series of enzymatic reactions culminating in the formation of holes in the target cell membrane and subsequent cell death. Activation of complement may also result in deposition of complement components on the target cell surface that facilitate ADCC by binding complement receptors (e.g., CR3) on leukocytes. To assess complement activation, a CDC assay, e.g., as described in Gazzano-Santoro et al., J. Immunol. Methods 202:163 (1996), can be performed. Polypeptide variants with altered Fc region amino acid sequences (polypeptides such as an antibody with a variant Fc region) and increased or decreased C1q binding capability are described, e.g., in U.S. Pat. No. 6,194,551 B1, U.S. Pat. No. 7,923,538, U.S. Pat. No. 7,994,290 and WO 1999/51642. See also, e.g., Idusogie et al., J. Immunol. 164: 4178-4184 (2000). [0145] The term “antibody-dependent cellular phagocytosis”, or simply “ADCP”, refers to the process by which antibody-coated cells are internalized, either in whole or in part, by phagocytic immune cells (e.g., macrophages, neutrophils and dendritic cells) that bind to an Fc region of Ig. [0146] A polypeptide variant with “altered” FcR binding affinity or ADCC activity (e.g., an antibody) is one which has either enhanced or diminished FcR binding activity and/or ADCC activity compared to a parent polypeptide or to a polypeptide comprising a native sequence Fc region. The polypeptide variant which “displays increased binding” to an FcR binds at least one FcR with better affinity than the parent polypeptide. The polypeptide variant which “displays decreased binding” to an FcR, binds at least one FcR with lower affinity than a parent polypeptide. In some embodiments, such variants which display decreased binding to an FcR may possess little or no appreciable binding to an FcR, e.g., 0- 20% binding to the FcR compared to a native sequence IgG Fc region. [0147] The term “substantially similar” or “substantially the same,” as used herein, denotes a sufficiently high degree of similarity between two or more numeric values such that one of skill in the art would consider the difference between the two or more values to be of little or no biological and/or statistical significance within the context of the biological characteristic measured by said value. In some embodiments the two or more substantially similar values differ by no more than about any one of 5%, 10%, 15%, 20%, 25%, or 50%. [0148] “Affinity” refers to the strength of the sum total of noncovalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured by common methods known in the art, including those described herein. [0149] An “autoimmune disease” as used herein refers to a disease or disorder arising from and directed against an individual’s own tissues or proteins. [0150] “Patient” as used herein refers to a subject to whom is administered a Ligand- Drug Conjugate compound of the present invention. Patient includes, but are not limited to, a human, rat, mouse, guinea pig, non-human primate, pig, goat, cow, horse, dog, cat, bird and fowl. Typically, the patient is a rat, mouse, dog, human or non-human primate, more typically a human. [0151] The terms “treat” or “treatment,” unless otherwise indicated by context, refer to therapeutic treatment and prophylactic wherein the object is to inhibit or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder. [0152] In the context of cancer, the term “treating” includes any or all of: killing tumor cells; inhibiting growth of tumor cells, cancer cells, or of a tumor; inhibiting replication of tumor cells or cancer cells, lessening of overall tumor burden or decreasing the number of cancerous cells, and ameliorating one or more symptoms associated with the disease. [0153] In the context of an autoimmune disease, the term “treating” includes any or all of: inhibiting replication of cells associated with an autoimmune disease state including, but not limited to, cells that produce an autoimmune antibody, lessening the autoimmune- antibody burden and ameliorating one or more symptoms of an autoimmune disease. [0154] “Compound” as the term is used herein, refers to and encompasses the chemical compound itself, either named or represented by structure, and salt form(s) thereof, whether explicitly stated or not, unless context makes clear that such salt forms are to be excluded. The term “compound” further encompasses solvate forms of the compound, in which solvent is noncovalently associated with the compound or is reversibly associated covalently with the compound, as when a carbonyl group of the compound is hydrated to form a gem-diol. Solvate forms include those of the compound itself and its salt form(s) and are inclusive of hemisolvates, monosolvates, disolvates, including hydrates; when a compound is associated with two or more solvent molecules, the two or more solvent molecules are the same or different. [0155] In some instances, a compound of the invention will include an explicit reference to one or more of the above forms, e.g., salts and solvates, which does not imply any solid state form of the compound; however, this reference is for emphasis only, and is not to be construed as excluding any other of the forms as identified above. Furthermore, when explicit reference to a salt and/or solvate form of a compound or a Ligand Drug Conjugate composition is not made, that omission is not to be construed as excluding the salt and/or solvate form(s) of the compound or Conjugate unless context make clear that such salt and/or solvate forms are to be excluded. [0156] The phrase “salt thereof” as the phrase is used herein, refers to a salt form of a compound (e.g., a Drug, a Drug-Linker compound or a Ligand-Drug Conjugate compound). A salt form of a compound is of one or more internal salt forms and/or involves the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion. The counterion in a salt form of a compound is typically an organic or inorganic moiety that stabilizes the charge on the parent compound. A salt form of a compound has one or more than one charged atom in its structure. In instances where multiple charged atoms are part of the salt form, multiple counter ions and/or multiple charged counter ions are present. Hence, a salt form of a compound typically has one or more charged atoms corresponding to those of the non-salt form of the compound and one or more counterions. In some aspects, the non- salt form of a compound contains at least one amino group or other basic moeity, and accordingly in the presence of an acid, an acid addition salt with the basic moiety is obtained. In other aspects, the non-salt form of a compound contains at least one carboxylic acid group or other acidic moiety, and accordingly in the presence of a base, a carboxylate or other anionic moiety is obtained. Exemplary salts include, but are not limited to, sulfate, trifluoroacetate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1’-methylene-bis- (2-hydroxy-3-naphthoate)) salts. [0157] A pharmaceutically acceptable salt is a salt form of a compound that is suitable for administration to a subject as described herein and in some aspects includes countercations or counteranions as described by P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zürich:Wiley-VCH/VHCA, 2002. [0158] A “Linker Unit” as used herein is a bifunctional moiety that connects or is capable of connecting a Drug Unit to a Ligand Unit in a Ligand-Drug Conjugate compound. The Linker Units of the present invention comprise two or more components selected from the group consisting of a Stretcher Unit which in some embodiments will have a Basic Unit; a Connector Unit; a Parallel Connector Unit; a Releasable Linker; and a Spacer Unit. [0159] “PEG”, “PEG Unit” or “polyethylene glycol” as used herein is an organic moiety comprising repeating ethylene-oxy subunits and is polydisperse, monodisperse, or discrete (i.e., having discrete number of ethylene-oxy subunits). Polydisperse PEGs are a heterogeneous mixture of sizes and molecular weights whereas monodisperse PEGs are typically purified from heterogeneous mixtures and are therefore provide a single chain length and molecular weight. Preferred PEG Units are discrete PEGs, compounds that are synthesized in stepwise fashion and not via a polymerization process. Discrete PEGs provide a single molecule with defined and specified chain length. [0160] The PEG Unit provided herein comprises one or multiple polyethylene glycol chains, each comprising one or more ethyleneoxy subunits, covalently attached to each other. The polyethylene glycol chains are linked together in any pattern (e.g., in a linear, branched, or star shaped configuration). Typically, at least one of the polyethylene glycol chains prior to incorporation into a Ligand-Drug Conjugate compound is derivitized at one end with an alkyl moiety substituted with an electrophilic group for covalent attachment to the carbamate nitrogen of a methylene carbamate unit (i.e., represents an instance of R). Typically, the terminal ethyleneoxy subunit in each polyethylene glycol chains not involved in covalent attachment to the remainder of the Linker Unit is modified with a PEG Capping Unit, typically H or an optionally substituted alkyl such as –CH3, -CH2CH3 or -CH2CH2CO2H. A preferred PEG Unit has a single polyethylene glycol chain with 4 to 24 –CH2CH2O- subunits covalently attached in series and terminated at one end with a PEG Capping Unit. [0161] “Halogen” as the term is used herein by itself or in combination with another term, unless otherwise stated or implied by context, refers to fluorine, chlorine, bromine or iodine and is typically -F or -Cl. [0162] Unless otherwise indicated, the term "alkyl" by itself or as part of another term refers to a straight chain or branched, saturated hydrocarbon having the indicated number of carbon atoms (e.g., “-C1-C4 alkyl,” “-C1-C8 alkyl,” or “-C1-C10 alkyl refer to an alkyl group having from 1 to 4, 1 to 8, or 1 to 10 carbon atoms, respectively). When the number of carbon atoms is not indicated, the alkyl group has from 1 to 8 carbon atoms. Representative straight chain “-C1-C8 alkyl” groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl and -n-octyl; while branched –C3-C8 alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and -2- methylbutyl. [0163] Unless otherwise indicated, "alkylene," by itself of as part of another term, refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of the stated number of carbon atoms, typically 1-4, 1-8, or 1-10 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to: methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. In preferred aspects, an alkylene is a branched or straight chain hydrocarbon (i.e., it is not a cyclic hydrocarbon). [0164] “Alkenyl” as the term is used herein, by itself or as part of another term, unless otherwise stated or implied by context, refers to an organic moiety, substituent or group that comprises one or more double bond functional groups (e.g., a -CH=CH- moiety) or 1, 2, 3, 4, 5 or 6 or more, typically 1, 2 or 3 of such functional groups, more typically one such functional group, and in some aspects may contain non-aromatic linked normal, secondary, tertiary or cyclic carbon atoms, i.e., linear, branched, cyclic or any combination thereof as part of the base moiety unless the alkenyl substituent, moiety or group is a vinyl moiety (e.g., a -CH=CH2 moiety). An alkenyl moiety, group or substituent having multiple double bonds may have the double bonds arranged contiguously (i.e., a 1,3-butadienyl moiety) or non- contiguously with one or more intervening saturated carbon atoms or a combination thereof, provided that a cyclic, contiguous arrangement of double bonds do not form a cyclic conjugated system of 4n + 2 electrons (i.e., is not aromatic). [0165] An alkenyl moiety, group or substituent contains at least one sp2 carbon atom in which that carbon atom is divalent and is doubly bonded to another organic moiety or Markush structure to which it is associated, or contains at least two sp2 carbon atoms in conjugation to each other in which one of the sp2 carbon atoms is monovalent and is singly bonded to another organic moiety or Markush structure to which it is associated. Typically, when alkenyl is used as a Markush group (i.e., is a substituent) the alkenyl is singly bonded to a Markush formula or another organic moiety with which it is associated through a sp2 carbon of an alkene functional group of the alkenyl moiety. In some aspects, when an alkenyl moiety is specified, species encompasses those corresponding to any of the optionally substituted alkyl or carbocyclyl, groups moieties or substituents described herein that has one or more endo double bonds in which a sp2 carbon atom thereof is monovalent and monovalent moieties derived from removal of a hydrogen atom from a sp2 carbon of a parent alkene compound. Such monovalent moieties are exemplified without limitation by vinyl (- CH=CH2), allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, and cyclohexenyl. In some aspects, the term alkenyl encompasses those and/or other linear, cyclic and branched chained, all carbon-containing moieties containing at least one double bond functional group in which one of the sp2 carbon atoms is monovalent. [0166] The number of carbon atoms in an alkenyl moiety is defined by the number of sp2 carbon atoms of the alkene functional group(s) that defines it as an alkenyl substituent and the total number of contiguous non-aromatic carbon atoms appended to each of these sp2 carbons not including any carbon atom of the other moiety or Markush structure for which the alkenyl moiety is a variable group and carbon atoms from any optional substituent to the alkenyl moiety. That number ranges from 1 to 50 or 1 to 30, typically 1 to 20 or 1 to 12, more typically, 1 to 8, 1 to 6 or 1 to 4 carbon atoms when the double bond functional group is doubly bonded to a Markush structure (e.g. =CH2), or ranges from 2 to 50, typically 2 to 30, 2 to 20 or 2 to 12, more typically 2 to 8, 2 to 6 or 2 to 4 carbon atoms, when the double bond functional group is singly bonded to the Markush structure (e.g., -CH=CH2). For example, C2-C8 alkenyl or C2-C8 alkenyl means an alkenyl moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms in which at least two are sp2 carbon atoms in conjugation with each other with one of these carbon atoms being monovalent, and C2-C6 alkenyl or C2-C6 alkenyl means an alkenyl moiety containing 2, 3, 4, 5 or 6 carbon atoms in which at least two are sp2 carbons that are in conjugation with each other with one of these carbon atoms being monovalent. In some aspects, an alkenyl substituent or group is a C2-C6 or C2-C4 alkenyl moiety having only two sp2 carbons that are in conjugation with each other with one of these carbon atoms being monovalent. Typically, an alkenyl substituent is a C2-C6 or C2-C4 alkenyl moiety having only two sp2 carbons that are in conjugation with each other. When the number of carbon atoms is not indicated, an alkenyl moiety has from 2 to 8 carbon atoms. [0167] “Alkenylene” as the term is used herein, by itself of as part of another term, unless otherwise stated or implied by context, refers to an organic moiety, substituent or group that comprises one or more double bond moieties, as previously described for alkenyl, of the stated number of carbon atoms and has two radical centers derived by the removal of two hydrogen atoms from the same or two different sp2 carbon atoms of an alkene functional group or removal of two hydrogen atoms from two separate alkene functional groups in a parent alkene. In some aspects, an alkenylene moiety is that of an alkenyl radical as described herein in which a hydrogen atom has been removed from the same or different sp2 carbon atom of a double bond functional group of the alkenyl radical, or from a sp2 carbon from a different double bonded moiety to provide a diradical. Typically, alkenylene moieties encompass diradicals containing the structure of –C=C- or –C=C-X1-C=C- wherein X1 is absent or is an alkylene as defined herein, which is typically a C1-C6 alkylene. The number of carbon atoms in an alkenylene moiety is defined by the number of sp2 carbon atoms of its alkene functional group(s) that defines it as an alkenylene moiety and the total number of contiguous non-aromatic carbon atoms appended to each of its sp2 carbons not including any carbon atoms of the other moiety or Markush structure in which the alkenyl moiety is a present as a variable group. That number, unless otherwise specified, ranges from 2 to 50 or 2 to 30, typically from 2 to 20 or 2 to 12, more typically from 2 to 8, 2 to 6 or 2 to 4 carbon atoms. For example, C2-C8 alkenylene or C2-C8 alkenylene means an alkenylene moiety containing 2, 3, 4, 5, 6, 7 or 8 carbon atoms, in which at least two are sp2 carbons in which one is divalent or both are monovalent, that are in conjugation with each other and C2-C6 alkenylene or C2-C6 alkenylene means an alkenyl moiety containing 2, 3, 4, 5 or 6 carbon atoms in which at least two are sp2 carbons, in which at least two are sp2 carbons in which one is divalent or both are monovalent, that are in conjugation with each other. In some aspects, an alkenylene moiety is a C2-C6 or C2-C4 alkenylene having two sp2 carbons that are in conjugation with each other in which both sp2 carbon atoms are monovalent. When the number of carbon atoms is not indicated, an alkenylene moiety has from 2 to 8 carbon atoms. [0168] “Alkynyl” as the term is used herein, by itself or as part of another term, unless otherwise stated or implied by context, refers to an organic moiety, substituent or group that comprises one or more triple bond functional groups (e.g., a -C≡C- moiety) or 1, 2, 3, 4, 5, or 6 or more, typically 1, 2, or 3 of such functional groups, more typically one such functional group. An alkynyl moiety, group or substituent having multiple triple bonds may have the triple bonds arranged contiguously or non-contiguously with one or more intervening saturated or unsaturated carbon atoms or a combination thereof, provided that a cyclic, contiguous arrangement of triple bonds do not form a cyclic conjugated system of 4n + 2 electrons (i.e., is not aromatic). [0169] An alkynyl moiety, group or substituent contains at least two sp carbon atom in which the carbon atoms are conjugation to each other and in which one of the sp carbon atoms is singly bonded, to another organic moiety or Markush structure to which it is associated. When alkynyl is used as a Markush group (i.e., is a substituent) the alkynyl is singly bonded to a Markush formula or another organic moiety with which it is associated through a triple-bonded carbon (i.e., a sp carbon) of a terminal alkyne functional group. In some aspects when an alkynyl moiety, group or substituent is specified, species encompasses are any of the alkyl or carbocyclyl, groups moieties or substituents described herein that has one or more endo triple bonds and monovalent moieties derived from removal of a hydrogen atom from a sp carbon of a parent alkyne compound. Such monovalent moieties are exemplified without limitation by -C≡CH, and -C≡C-CH3, and -C≡C-Ph. [0170] The number of carbon atoms in an alkynyl substituent is defined by the number of sp carbon atoms of the alkene functional group that defines it as an alkynyl substituent and the total number of contiguous non-aromatic carbon atoms appended to each of these sp carbons not including any carbon atom of the other moiety or Markush structure for which the alkenyl moiety is a variable group. That number can vary ranging from 2 to 50, typically 2 to 30, 2 to 20, or 2 to 12, more typically 2 to 8, 2 to 6, or 2 to 4 carbon atoms, when the triple bond functional group is singly bonded to the Markush structure (e.g., -CH≡CH). For example, C2-C8 alkynyl or C2-C8 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms in which at least two are sp carbon atoms in conjugation with each other with one of these carbon atoms being monovalent, and C2-C6 alkynyl or C2-C6 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, or 6 carbon atoms in which at least two are sp carbons that are in conjugation with each other with one of these carbon atoms being monovalent. In some aspects, an alkynyl substituent or group is a C2-C6 or C2-C4 alkynyl moiety having two sp carbons that are in conjugation with each other with one of these carbon atoms being monovalent. When the number of carbon atoms is not indicated, an alkynyl moiety, group or substituent has from 2 to 8 carbon atoms. [0171] The term “Prodrug” as used herein refers to a less biologically active or inactive compound which is transformed within the body into a more biologically active compound via a chemical or biological process (i.e., a chemical reaction or an enzymatic biotransformation). Typically, a biologically active compound is rendered less biologically active (i.e., is converted to a prodrug) by chemically modifying the compound with a prodrug moiety. In some aspects, the prodrug is a Type II prodrug, which are bioactivated outside cells, e.g., in digestive fluids, or in the body's circulation system, e.g., in blood. Exemplary prodrugs are esters and β-D-glucopyranosides. [0172] Unless otherwise indicated, "aryl," by itself or as part of another term, means amonovalent carbocyclic aromatic hydrocarbon radical of the stated number of carbon atoms, typically 6-20 carbon atoms, derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as “Ar”. Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. An exemplary aryl group is a phenyl group. [0173] Unless otherwise indicated, an “arylene,” by itself or as part of another term, is an aryl group as defined above which has two covalent bonds (i.e., it is divalent) and is in the ortho, meta, or para orientations as shown in the following structures, with phenyl as the exemplary group:
Figure imgf000056_0001
[0174] Unless otherwise indicated, a “C3-C8 heterocycle,” by itself or as part of another term, refers to a monovalentaromatic or non-aromatic monocyclic or bicyclic ring system having from 3 to 8 carbon atoms (also referred to as ring members) and one to four heteroatom ring members independently selected from N, O, P or S, and derived by removal of one hydrogen atom from a ring atom of a parent ring system. In some aspects, one or more N, C or S atoms in the heterocycle is/are oxidized. In some aspects, the ring that includes the heteroatom is aromatic or nonaromatic. Heterocycles in which all the ring atoms are involved in aromaticity are referred to as heteroaryls and otherwise are referred to heterocarbocycles. [0175] Unless otherwise noted, the heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. In some aspects, a heteroaryl is bonded through an aromatic carbon of its aromatic ring system, referred to as a C-linked heteroaryl. In other aspects, a heteroaryl is bonded through a non-double-bonded N atom (i.e., not =N-) in its aromatic ring system, which is referred to as an N-linked heteroaryl. Thus, nitrogen-containing heterocycles are C-linked or N-linked and include pyrrole moieties, such as pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked), and imidazole moieties such as imidazol-1-yl and imidazol-3-yl (both N-linked), and imidazol-2-yl, imidazol-4-yl and imidazol-5-yl moieties (all of which are C-linked). [0176] Unless otherwise indicated, a“C3-C8 heteroaryl,” is an aromatic C3-C8 heterocycle in which the subscript denotes the total number of carbons of the cyclic ring system of the heterocycle or the total number of aromatic carbons of the aromatic ring system of the heteroaryl and does not implicate the size of the ring system or the presence or absence of ring fusion. Representative examples of a C3-C8 heterocycle include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, pyrrolyl, thiophenyl (thiophene), furanyl, thiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, isothiazolyl, and isoxazolyl. [0177] When explicitly given, the size of the ring system of a heterocycle or heteroaryl is indicated by the total number of atoms in the ring. For example, designation as a 5- or 6- membered heteroaryl indicates the total number of aromatic atoms (i.e., 5 or 6) in the heteroaromatic ring system of the heteroaryl but does not imply the number of aromatic heteroatoms or the number of aromatic carbon atoms in that ring system. Fused heteroaryls are explicitly stated or implied by context as such and are typically indicated by the number of aromatic atoms in each aromatic ring that are fused together to make up the fused heteroaromatic ring system. For example, a 5,6-membered heteroaryl is an aromatic 5- membered ring fused to an aromatic 6-membered ring in which one or both rings have aromatic heteroatom(s) or where a heteroatom is shared between the two rings. [0178] A heterocycle fused to an aryl or heteroaryl such that the heterocycle remains non- aromatic and is part of a larger structure through attachment with the non-aromatic portion of the fused ring system is an example of a heterocycle in which the heterocycle is substituted by ring fusion with the aryl or heteroaryl. Likewise, an aryl or heteroaryl fused to heterocycle or carbocycle that is part of a larger structure through attachment with the aromatic portion of the fused ring system is an example of an aryl or heterocycle in which the aryl or heterocycle is substituted by ring fusion with the heterocycle or carbocycle. [0179] Unless otherwise indicated, “C3-C8 heterocyclo,” by itself or as part of another term, refers to a C3-C8 heterocyclic defined above wherein one of the hydrogen atoms of the heterocycle is replaced with a bond (i.e., it is divalent). Unless otherwise indicated, a “C3-C8 heteroarylene,” by itself or as part of another term, refers to a C3-C8 heteroaryl group defined above wherein one of the heteroaryl group’s hydrogen atoms is replaced with a bond (i.e., it is divalent). When explicitly given, the size of the ring system of a heteroarylene is indicated by the total number of atoms in the ring. For example, designation as a 5- or 6-membered heteroarylene indicates the total number of atoms (i.e., 5 or 6) in the heterocyclic ring system of the heterocycle, but does not imply the number of heteroatoms or the number of carbon atoms in that ring system. [0180] Unless otherwise indicated, a “C3-C8 carbocycle,” by itself or as part of another term, is a 3-, 4-, 5-, 6-, 7- or 8-membered monovalent,saturated or unsaturated non-aromatic monocyclic or bicyclic carbocyclic ring derived by the removal of one hydrogen atom from a ring atom of a parent ring system. Representative -C3-C8 carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5- cycloheptatrienyl, cyclooctyl, and cyclooctadienyl. [0181] Unless otherwise indicated, a “C3-C8 carbocyclo,” by itself or as part of another term, refers to a C3-C8 carbocycle group defined above wherein another one of the carbocycle group’s hydrogen atoms is replaced with a bond (i.e., it is divalent). [0182] Unless otherwise indicated, the term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain hydrocarbon, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to ten, preferably one to three, heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatom(s) O, N and S are placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. The heteroatom Si is placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. When explicitly given, the number of atoms in a heteroalkyl or heteroarylene is indicated by the total number of atoms in the group. For example, designation as a C1-C2 heteroalkyl indicates the total number of atoms (i.e., 1 or 2) in the heteroalkyl group, but does not imply the number of heteroatoms or the number of carbon atoms in that group. [0183] Examples include –CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)- CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -NH-CH2-CH2-NH-C(O)-CH2-CH3, -CH2- CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-O-CH3, and –CH=CH-N(CH3)- CH3. In some aspects, two heteroatoms are consecutive, such as, for example, -CH2-NH- OCH3 and –CH2-O-Si(CH3)3. Typically, a C1 to C4 heteroalkyl or heteroalkylene has 1 to 4 carbon atoms and 1 or 2 heteroatoms and a C1 to C3 heteroalkyl or heteroalkylene has 1 to 3 carbon atoms and 1 or 2 heteroatoms. In some aspects, a heteroalkyl or heteroalkylene is saturated. [0184] Unless otherwise indicated, the term "heteroalkylene" by itself or in combination with another term means a divalent group derived from heteroalkyl (as discussed above), as exemplified by –CH2-CH2-S-CH2-CH2- and –CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini. Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied. [0185] Unless otherwise indicated, “aminoalkyl” by itself or in combination with another term means a heteroalkyl wherein an alkyl moiety as defined herein is substituted with an amino, alkylamino, dialkylamino or cycloalkylamino group. Exemplary non-limiting aminoalkyls are –CH2NH2, -CH2CH2NH2, -CH2CH2NHCH3 and -CH2CH2N(CH3)2 and further includes branched species such as –CH(CH3)NH2 and -C(CH3)CH2NH2 in the (R)- or (S)- configuration. Alternatively, an aminoalkyl is an alkyl moiety, group, or substituent as defined herein wherein a sp3 carbon other than the radical carbon atom of the alkyl moiety has been replaced with an amino or alkylamino moiety wherein its sp3 nitrogen atom replaces the sp3 carbon of the alkyl moiety provided that at least one sp3 carbon atom of the alkyl moiety remains. When referring to an aminoalkyl moiety as a substituent to a larger structure or another moiety the aminoalkyl is covalently attached to the structure or moiety through the carbon radical of the alkyl moiety of the aminoalkyl. [0186] “Hydroxyalkyl” as the term is used herein by itself or in combination with another term, unless otherwise stated or implied by context, refers to an alkyl moiety, group, or substituent having a hydroxyl radical in place of one or more hydrogen atoms of the alkyl moiety, group, or substituent. In some aspects, one or two hydrogen atoms are each replaced with a hydroxyl substituent in a hydroxyalkyl group. A hydroxyalkyl is typically denoted by the number of contiguous carbon atoms of its alkyl or alkylene moiety. Thus, a C1 hydroxyalkyl is exemplified without limitation by –CH2OH, and a C2 hydroxyalkyl is exemplified without limitation by –CH2CH2OH or –CH2(OH)CH3. [0187] “Haloalkyl” as the term is used herein by itself or in combination with another term, unless otherwise stated or implied by context, referes to an alkyl moiety, group, or substituent having a halogen in place of one or more hydrogen atoms of the alkyl moiety, group, or substituent. In some aspects, one or two hydrogen atoms are each replaced with a halogen in a haloalkyl group. A haloalkyl is typically denoted by the number of contiguous carbon atoms of its alkyl or alkylene moiety. Thus, a C1 haloalkyl is exemplified without limitation by –CH2F, –CH2Cl, –CH2Br, or –CH2I, and a C2 haloalkyl is exemplified without limitation by –CH2CH2F, –CH2CH2Cl, –CH2CH2Br, –CH2CH2I, –CH2(F)CH3, –CH2(Cl)CH3, –CH2(Br)CH3, or –CH2(I)CH3. In some embodiments, the term “haloalkyl” refers to an alkyl moiety, group, or substituent having halogens in place of two or more hydrogen atoms. For example, a C1 haloalkyl is also exemplified without limitation by –CHF2, –CHCl2, –CHBr2, or –CHI2, and a C2 haloalkyl is exemplified without limitation by –CH2CHF2, –CH2CHCl2, – CH2CHBr2, –CH2CHI2, –CH(F)2CH3, –CH(Cl)2CH3, –CH(Br)2CH3, or –CH(I)2CH3. In some aspects, the term “haloalkyl” refers to an alkyl moiety, group, or substituent having halogens in place of all hydrogen atoms. Thus, in some aspects, the term “haloalkyl” encompasses fully halogenated alkyl moieties, groups, or substituents. For example, a C1 haloalkyl is also exemplified without limitation by –CF3, –CCl3, –CBr3, or –CI3. [0188] Unless otherwise indicated “alkylamino” and “cycloalkylamino” by itself or in combination with another term means an alkyl or cycloalkyl radical, as described herein, wherein the radical carbon atom of the alkyl or cycloalkyl radical has been replaced with a nitrogen radical, provided that at least one sp3 carbon atom of the alkyl or cycloalkyl radical remains. In those instances where the alkylamino is substituted at its nitrogen with another alkyl moiety the resulting substituted radical is sometimes referred to as a dialkylamino moiety, group or substituent wherein the alkyl moieties substituting nitrogen are independently selected. [0189] Exemplary and non-limiting amino, alkylamino and dialkylamino substituents, include those having the structure of –N(R’)2, wherein R’ in these examples are independently hydrogen or C1-6 alkyl, typically hydrogen or methyl, whereas in cycloalkyl amines, which are included in heterocycloalkyls, both R’ together with the nitrogen to which they are attached define a heterocyclic ring. When both R’ are hydrogen or alkyl, the moiety is sometimes described as a primary amino group and a tertiary amine group, respectively. When one R’ is hydrogen and the other is alkyl, then the moiety is sometimes described as a secondary amino group. Primary and secondary alkylamino moieties are typically more reactive as nucleophiles towards carbonyl-containing electrophilic centers whereas tertiary amines are typically more basic. [0190] The term “substituted” means that the specified group or moiety bears one or more substituents. Typical substituents include, but are not limited to a -X, -R'', -OH, -OR'', -SR'', , -N(R'')2, -N(R'')3, =NR'', -CX3, -CN, -NO2, -NR''C(=O)R'', - C(=O)R'', -C(=O)N(R'')2, -S(=O)2R'', -S(=O)2NR'', -S(=O)R'', -OP(=O)(OR'')2, -P(=O)(OR'')2, - PO3 =, PO3H2, -C(=O)R'', -C(=S)R'', -CO2R'', -CO2-, -C(=S)OR'', -C(=O)SR'', -C(=S)SR'', - C(=O)N(R'')2, -C(=S)N(R'')2, and -C(=NR)N(R'')2, where each X is independently selected from the group consisting of a halogen: -F, -Cl, -Br, and -I; and wherein each R'' is independently selected from the group consisting of -H, -C1-C20 alkyl, -C6-C20 aryl, -C3-C14 heterocycle, a protecting group, and a prodrug moiety. [0191] More typically substituents are selected from the group consisting of -X, -R'', -OH, -OR'', -SR'', -N(R'')2, -N(R'')3, =NR'', -NR''C(=O)R'', -C(=O)R'', - C(=O)N(R'')2, -S(=O)2R'', -S(=O)2NR'', -S(=O)R'', -C(=O)R'', -C(=S)R'', -C(=O)N(R'')2, - C(=S)N(R'')2, and -C(=NR)N(R'')2, wherein each X is independently selected from the group consisting of –F and -Cl, or are selected from the group consisting of -X, -R'', -OH, -OR'', - N(R'')2, -N(R'')3, -NR''C(=O)R'', -C(=O)N(R'')2, -S(=O)2R'', -S(=O)2NR'', -S(=O)R'', - C(=O)R'', -C(=O)N(R'')2, -C(=NR)N(R'')2, a protecting group, and a prodrug moiety, wherein each X is –F; and wherein each R is independently selected from the group consisting of hydrogen, -C1-C20 alkyl, -C6-C20 aryl, -C3-C14 heterocycle, a protecting group, and a prodrug moiety. [0192] In some aspects, a substituent on an alkyl, alkenyl, or alkynyl is selected from the group consisting -N(R'')2, -N(R'')3 and -C(=NR)N(R'')2, wherein R'' is selected from the group consisting of hydrogen and -C1-C20 alkyl. In other aspects, alkyl, alkenyl, or alkynyl is substituted with a series of ethyleneoxy moieties to define a PEG Unit as described herein. In some embodiments, alkylene, carbocycle, carbocyclo, arylene, heteroalkyl, heteroalkylene, heterocycle, heterocyclo, heteroaryl, and heteroarylene groups as described above are similarly substituted. [0193] The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted is used to described a structural system, the substitution is meant to occur at any valency-allowed position on the system. When a group or moiety bears more than one substituent, it is understood that the substituents may be the same or different from one another. In some embodiments a substituted group or moiety bears from one to five substituents. In some embodiments a substituted group or moiety bears one substituent. In some embodiments a substituted group or moiety bears two substituents. In some embodiments a substituted group or moiety bears three substituents. In some embodiments a substituted group or moiety bears four substituents. In some embodiments a substituted group or moiety bears five substituents. [0194] By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and/or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted. [0195] “Protecting group” as used here means a moiety that prevents or reduces the ability of the atom or functional group to which it is linked from participating in unwanted reactions. Typical protecting groups for atoms or functional groups are given in Greene (1999), “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 3RD ED.”, Wiley Interscience, which is incorporated by reference herein. Protecting groups for heteroatoms such as oxygen, sulfur and nitrogen are used in some instances to minimize or avoid unwanted their reactions with electrophilic compounds. In other instances, the protecting group is used to reduce or eliminate the nucleophilicity and/or basicity of the unprotected heteroatom. Non-limiting examples of protected oxygen are given by -ORPR, wherein RPR is a protecting group for hydroxyl, wherein hydroxyl is typically protected as an ester (e.g. acetate, propionate or benzoate). Other protecting groups for hydroxyl avoid interfering with the nucleophilicity of organometallic reagents or other highly basic reagents, where hydroxyl is typically protected as an ether, including alkyl or heterocycloalkyl ethers, (e.g., methyl or tetrahydropyranyl ethers), alkoxymethyl ethers (e.g., methoxymethyl or ethoxymethyl ethers), optionally substituted aryl ethers, and silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), tert- butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS), triisopropylsilyl (TIPS) and [2-(trimethylsilyl)ethoxy]-methylsilyl (SEM)). Nitrogen protecting groups include those for primary or secondary amines as in -NHRPR or -N(RPR)2-, wherein least one of RPR is a nitrogen atom protecting group or both RPR together comprise a protecting group. [0196] A protecting group is suitable when it is capable of preventing or avoiding unwanted side-reactions or premature loss of the protecting group under reaction conditions required to effect desired chemical transformation elsewhere in the molecule and during purification of the newly formed molecule when desired, and are removable under conditions that do not adversely affect the structure or stereochemical integrity of that newly formed molecule. By way of example and not limitation, a suitable protecting group includes those previously described for protecting otherwise reactive functional groups. A suitable protecting group is sometimes a protecting group used in peptide coupling reactions. [0197] “Electron withdrawing group” as used herein means a functional group or electronegative atom that draws electron density away from an atom to which it is bonded either inductively and/or through resonance, whichever is more dominant (i.e., in some aspects, a functional group or atom is electron withdrawing inductively but is overall electron donating through resonance) and tends to stabilize anions or electron-rich moieties. The electron withdrawing effect is typically transmitted inductively, albeit in attenuated form, to other atoms attached to the bonded atom that has been made electron deficient by the electron withdrawing group (EWG), thus affecting the electrophilicity of a more remote reactive center. Exemplary electron withdrawing groups include, but are not limited to -C(=O), -CN, -NO2, -CX3, -X, -C(=O)OR, -C(=O)N(R)2, -C(=O)R, -C(=O)X, -S(=O)2R, -S(=O)2OR, - S(=O)2NHR, -S(=O)2N(R)2, -P(=O)(OR)2, -P(=O)(CH3)NHR, -NO, -N(R)3 +, wherein X is -F, -Br, -Cl, or -I, and R in some aspects is, at each occurrence, independently selected from the group consisting of hydrogen and C1-6 alkyl, and certain O-linked moieties as described herein such as acyloxy. [0198] Exemplary EWGs can also include aryl groups (e.g., phenyl) depending on substitution of its aromatic ring and certain heteroaryl groups (e.g., pyridine). Thus, the term “electron withdrawing groups” also includes aryls or heteroaryls that are further substituted with electron withdrawing groups. Typically, electron withdrawing groups on aryls or heteroaryls are -C(=O), -CN, -NO2, -CX3, and –X, wherein X independently selected is halogen, typically –F or -Cl. Depending on their substituents, an alkyl moiety may also be an electron withdrawing group. [0199] “Succinimide moiety” as used herein refers to an organic moiety comprising a succinimide ring system, which is present in one type of Stretcher Unit (Z) that typically further comprises an alkylene-containing moiety bonded to the imide nitrogen of that ring system. A succinimide moiety typically results from Michael addition of a sulfhydryl group of a Ligand Unit to the maleimide ring system of a Stretcher Unit precursor (Z') in a Drug Linker compound or maleimide-containing intermediate thereof. A succinimide moiety therefore comprises a thio-substituted succinimide ring system and when present in a Ligand- Drug Conjugate compound has its imide nitrogen substituted with the remainder of the Linker Unit of the Ligand-Drug Conjugate compound and is optionally substituted with substituent(s) that were present on the maleimide ring system of Z'. [0200] “Succinic acid-amide moiety” as used herein refers to a succinic acid moiety wherein one of the two carboxylic acid groups is replaced with an amide substituent that results from the thio-substituted succinimide ring system of a succinimide moiety as defined herein having undergone breakage of one of its carbonyl-nitrogen bonds by hydrolysis. In some aspects, the succinic acid-amide moiety has the structure:
Figure imgf000064_0001
wherein the wavy line on the left indicates attachment to a Ligand Unit or hydrogen atom and the wavy line on the right indicates attachment to the remainder of a Ligand-Drug Conjugate compound, Drug-Linker compound, intermediate, or fragment thereof. Hydrolysis resulting in a succinic acid-amide moiety provides a Linker Unit less likely to suffer premature loss of the Ligand Unit to which it is bonded through elimination of the antibody-thio substituent. Hydrolysis of the succinimide ring system of the thio-substituted succinimide moiety is expected to provide regiochemical isomers of acid-amide moieties that are due to differences in reactivity of the two carbonyl carbons of the succinimide ring system attributable at least in part to any substituent present in the maleimide ring system of the Stretcher Unit precursor and to the thio substituent introduced by the targeting ligand, which is a precursor to the Ligand Unit. [0201] In many instances, the assembly of the conjugates, linkers and components described herein will refer to reactive groups. A “reactive group” or RG is a group that contains a reactive site (RS) capable of forming a bond with either the components of the Linker Unit Q or the Drug Unit D. RS is the reactive site within a Reactive Group (RG). Reactive groups include sulfhydryl groups to form disulfide bonds or thioether bonds, aldehyde, ketone, or hydrazine groups to form hydrazone bonds, carboxylic or amino groups to form peptide bonds, carboxylic or hydroxy groups to form ester bonds, sulfonic acids to form sulfonamide bonds, alcohols to form carbamate bonds, and amines to form sulfonamide bonds or carbamate bonds. [0202] The following table is illustrative of Reactive Groups, Reactive Sites, and exemplary functional groups capable of forming after reaction of the reactive site. The table is not limiting. One of skill in the art will appreciate that the noted R* and R** portions in the table are effectively any organic moiety (e.g., an alkyl group, aryl group, heteroaryl group, or substituted alkyl, aryl, or heteroaryl, group) that is compatible with the bond formation provided in converting RG to one of the Exemplary Functional Groups. It will also be appreciated that, as applied to the various aspects of the present invention, R* represents one or more components of the self-stabilizing linker or optional secondary linker, and R** represents one or more components of the optional secondary linker, Drug Unit, stabilizing unit, or detection unit.
Figure imgf000065_0001
II. Embodiments Auristatin Compounds [0203] The present application is based, in part, on the surprising discovery that it is possible to improve the properties of auristatin-containing Ligand-Drug Conjugate compounds by tuning the hydrophilicity of auristatin drugs with polar moieities, e.g., hydroxyl groups. The hydrophobicity of auristatin drugs is a known barrier to their implementation in pharmaceuticals, including Ligand-Drug Conjugates, due to the potential for off-target toxicity due to high bystander activity and rapid clearance of the drug from the body of subjects. The compounds of the present application attenuate the hydphobicity of the Drug Unit, which in turn attentuates the off-target toxicity and rapid clearance of the drugs. The use of Drug Units with polar moieities in certain locations on the auristatin backbone leads to decreased permeability and on-cell potency of the free drug, and thus fewer off-target effects during treatment, without sacrificing efficacy of intact Ligand-Drug Conjugate compounds that incorporate the Drug Units. [0204] In some embodiments herein, provided are auristatin compounds comprising at least one polar moiety on the auristatin backbone. In some embodiments, provided herein are Drug-Linker compounds comprising an auristatin moiety, as described herein. In some embodiments, provided herein are Ligand-Drug Conjugate compounds comprising an auristatin moiety, as described herein. In some embodiments, provided herein are methods of treating cancer using the Ligand-Drug Conjugate compounds described herein. In some embodiments, provided are methods of making auristatin compounds comprising at least one hydrophilic moiety, Drug-Linkers thereof and their intermediates, and Ligand-Drug Conjugate compounds thereof. In some embodiments, the polar moiety is a polar moiety other than carboxylate. In some embodiments, the polar moiety is a hydroxyl group. [0205] In some embodiments, provided is a compound of formula (I):
Figure imgf000066_0001
or a salt thereof, wherein Xb is -NR1R2; and Xa is
Figure imgf000066_0004
or Xa and Xb are taken together with the carbon atom to which they are attached to form
Figure imgf000066_0002
, wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups; R1, R2, R3, R4, Ra, Rb, R5, and R10 are each independently H or C1-C4 alkyl; X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; and q is 0 or 1, wherein when X is H, at least two of R7, R8, R9, and R11 comprise an OH moiety. [0206] In some embodiments, provided is a compound of formula (Iz):
Figure imgf000066_0003
(Iz) or a salt thereof, wherein Xb is -NR1R2; and Xa is
Figure imgf000067_0003
or Xa and Xb are taken together with the carbon atom to which they are attached to form
Figure imgf000067_0001
, wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups; R1, R2, R3, R4, Ra, Rb, R5, and R10 are each independently H or C1-C4 alkyl; X is OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; and q is 0 or 1. [0207] In some embodiments, provided is compound of Formula (II):
Figure imgf000067_0002
or a salt thereof, wherein R1, R3, and R4 are independently H or C1-C4 alkyl; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, or 2; and q is 0 or 1. [0208] In some embodiments of Formula (I), q is 0. In some embodiments of Formula (I), q is 1. In some embodiments of Formula (II), q is 0. In some embodiments of Formula (II), q is 1. [0209] In some embodiments of Formula (I) or (Iz), Xb is -NR1R2 is and Xa is
Figure imgf000068_0001
. In some embodiments, R1 and R2 are each independently C1-C4 alkyl. In some embodiments, R1 and R2 are both H. In some embodiments, R1 and R2 are each independently n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R1 and R2 are each independently ethyl or methyl. In some embodiments, R1 and R2 are both methyl. In some embodiments, R1 is H and R2 is C1-C4 alkyl. In some embodiments, R1 is H and R2 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R1 is H and R2 is ethyl or methyl. In some embodiments, R1 is H and R2 is methyl. In some emodiments, R3 and R4 are each independently C1-C4 alkyl. In some embodiments, R3 is H and R4 is C1-C4 alkyl. In some embodiments, R3 and R4 are H. In some embodiments, R3 is H and R4 is methyl. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, R1 is H, R2 is methyl, R3 is H, R4 is H, and n is 0. In some embodiments, R1 is methyl, R2 is methyl, R3 is H, R4 is H, and n is 0. [0210] In some embodiments of Formula (I) or (Iz), Xa and Xb are taken together with the carbon atom to which they are attached to form
Figure imgf000068_0002
, wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups. In some embodiments, R5 is H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R5 is H, ethyl, or methyl. In some embodiments, R5 is H or methyl. In some embodiments, R5 is ethyl or methyl. In some embodiments, R5 is H. In some embodiments, R5 is ethyl. In some embodiments, R5 is methyl. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 2. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 0 or 1 and m is 0, 1, or 2. In some embodiments, n is 0 and m is 2. In some embodiments, n is 1 and m is 1. In some embodiments, m is 2 and n is 1. In some embodiments, X is H or OH. In some embodiments, X is H. In some embodiments, X is OH. [0211] In some embodiments of Formula (I), X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra, -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH, -S(O)2Ra, -S(O)-Ra, -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is H or OH. In some embodiments, X is OH. In some embodiments, X is OH, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is H, OH, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is H, OH, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is H, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is H, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is H, OH, or -C(O)NRaRb. In some embodiments, X is OH or -C(O)NRaRb. In some embodiments, X is H or -C(O)NRaRb. In some embodiments, Ra and Rb are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra and Rb are independently H, ethyl, or methyl. In some embodiments, Ra and Rb are independently H or methyl. In some embodiments, Ra is H and Rb is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra is H and Rb is methyl. [0212] In some embodiments of Formula (Iz), X is OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra, -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH. In some embodiments, X is OH, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is OH or -C(O)NRaRb. In some embodiments, X is -C(O)NRaRb. In some embodiments, Ra and Rb are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra and Rb are independently H, ethyl, or methyl. In some embodiments, Ra and Rb are independently H or methyl. In some embodiments, Ra is H and Rb is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra is H and Rb is methyl. [0213] In some embodiments of Formula (I) or (Iz), Xb is -NR1R2 is and Xa is X is OH, R1 is H or methyl, R2 is methyl, R3 is H, R4 is H, and n is 0. In some
Figure imgf000069_0001
embodiments, X is OH, R1 is methyl, R2 is methyl, R3 is H, R4 is H, and n is 0. In some embodiments, X is OH, R1 is H, R2 is methyl, R3 is H, R4 is H, and n is 0. In some embodiments, X is OH, R3 and R4 are H, and n is 0. In some embodiments, X is OH, R1 is H, R2 is H, R3 is H, R4 is H, and n is 0. [0214] In some embodiments of Formula (II), R1 is H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R1 is H, ethyl, or methyl. In some embodiments, R1 is H or methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is methyl. In some embodiments, R1 is H. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0. [0215] In some embodiments of Formula (II), R3 and R4 are H. In some embodiments, R3 and R4 are methyl. In some embodiments, R3 is H and R4 is methyl. [0216] In some embodiments or Formula (I), (Iz), or (II), R6 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R6 is ethyl or methyl. In some embodiments, R6 is isopropyl. In some embodiments, R6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R6 is isopropyl substituted with OH. In some embodiments, R6 is ethyl substituted with OH. In some embodiments, R6 is methyl substituted with OH. [0217] In some embodiments of Formula (I), (Iz), or (II), R7 is C1-C4 alkyl substituted with OH. In some embodiments, R7 is C1-C4 alkyl subsituted by two OH moieties. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R7is C1-C4 alkyl. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R7 is methyl. In some embodiments, R7 is -CH2CH2OH or CH2OH. In some embodiments, R7 is -CH2OH. In some embodiments, R7 is 5-6 membered heteroaryl. In some embodiments, R7 is 5-membered heteroaryl. In some embodiments, R7 is thiazolyl. [0218] In some embodiments of Formula (I), (Iz), or (II), R8, R9, and R11 are H. In some embodiments, R8 is OH, R9 is H, and R11 is H. In some embodiments, R8 and R9 are each OH and R11 is H. In some embodiments, R8 is OH, R9 is H, and R11 is OH. In some embodiments, R8 is H, R9 is H, and R11 is OH. [0219] In some embodiments of Formula (I), (Iz), or (II), E is a 6-membered ring. In some embodiments, E is pyridine or phenyl. In some embodiments, E is phenyl. [0220] In some embodiments of Formula (I), (Iz), or (II), R7 is -CH2OH, R8 is H, R9 is H, and E is phenyl. [0221] In some embodiments, provided is a compound of Formula (Ia):
Figure imgf000071_0001
or a salt thereof, wherein R1, R2, R3, R4, Ra, and Rb are each independently H or C1-C4 alkyl; X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R6 is C1-C4 alkyl; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; q is 0 or 1; and wherein when X is H, at least two of R7, R8, R9, and R11 comprise an OH moiety. [0222] In some embodiments of Formula (Ia), q is 0. In some embodiments, q is 1. [0223] In some embodiments of Formula (Ia), R1 is H and R2 is C1-C4-alkyl. In some embodiments, R1 is H and R2 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R1 is H and R2 is ethyl or methyl. In some embodiments, R1 is H and R2 is methyl. In some embodiments, R1 and R2 are each independently C1-C4 alkyl. In some embodiments, R1 and R2 are each independently n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R1 and R2 are each independently ethyl or methyl. In some embodiments, R1 and R2 are methyl. In some embodiments, R1 and R2 are both H. [0224] In some embodiments of Formula (Ia), X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)- Ra, -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH, -S(O)2Ra, -S(O)-Ra, -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is H or OH. In some embodiments, X is OH. In some embodiments, X is OH, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is H, OH, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is H, OH, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is H, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is H, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is H, OH, or -C(O)NRaRb. In some embodiments, X is OH or -C(O)NRaRb. In some embodiments, X is H or -C(O)NRaRb. In some embodiments, Ra and Rb are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra and Rb are independently H, ethyl, or methyl. In some embodiments, Ra and Rb are independently H or methyl. In some embodiments, Ra is H and Rb is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra is H and Rb is methyl. [0225] In some embodiments of Formula (Ia), X is OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra, -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH. In some embodiments, X is OH, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is OH or -C(O)NRaRb. In some embodiments, X is -C(O)NRaRb. In some embodiments, Ra and Rb are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra and Rb are independently H, ethyl, or methyl. In some embodiments, Ra and Rb are independently H or methyl. In some embodiments, Ra is H and Rb is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra is H and Rb is methyl. [0226] In some embodiments of Formula (Ia), R6 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R6 is ethyl or methyl. In some embodiments, R6 is isopropyl. In some embodiments, R6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R6 is isopropyl substituted with OH. In some embodiments, R6 is ethyl substituted with OH. In some embodiments, R6 is methyl substituted with OH. [0227] In some embodiments of Formula (Ia), R7 is C1-C4 alkyl substituted with OH. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R7 is -CH2CH2OH or CH2OH. In some embodiments, R7 is -CH2OH. In some embodiments, R7 is C1-C4 alkyl. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R7 is methyl. In some embodiments, R7 is 5-6 membered heteroaryl. In some embodiments, R7 is 5-membered heteroaryl. In some embodiments, R7 is thiazolyl. [0228] In some embodiments of Formula (Ia), R8, R9, and R11 are H. In some embodiments, R8 is OH, R9 is H, and R11 is H. In some embodiments, R8 and R9 are each OH and R11 is H. In some embodiments, R8 is OH, R9 is H, and R11 is OH. [0229] In some embodiments of Formula (Ia), X is OH, R3 is H or methyl, R1 is H or C1- C4 alkyl, R2 is C1-C4 alkyl, R6 is C1-C4 alkyl, R7 is C1-C4 alkyl optionally substituted with OH, R8 is H or C1-C4 alkyl, R9 is H, and q is 0. In some embodiments, X is OH, R3 is H, R1 is H or methyl, R2 is methyl, R6 is isopropyl, R7 is CH2OH, R8 is H, R9 is H, and q is 0. [0230] In some embodiments, provided is a compound of Formula (Ib):
Figure imgf000073_0001
or a salt thereof, wherein the variables are as defined for Formula (I). [0231] In some embodiments of Formula (Ib), X is H. In some embodiments, X is H or OH. In some embodiments, R5 is H or methyl. In some embodiments, R5 is H. In some embodiments, m is 1 or 2. In some embodiments, m is 2. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, m is 2 and n is 0. In some embodiments, m is 1 and n is 1. [0232] In some embodiments or Formula (Ib), R6 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R6 is ethyl or methyl. In some embodiments, R6 is isopropyl. In some embodiments, R6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R6 is isopropyl substituted with OH. In some embodiments, R6 is ethyl substituted with OH. In some embodiments, R6 is methyl substituted with OH. [0233] In some embodiments of Formula (Ib), R7 is C1-C4 alkyl substituted with OH. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl, each of which substituted with OH. In some embodiments, R7is C1-C4 alkyl. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R7 is methyl. In some embodiments, R7 is -CH2CH2OH or CH2OH. In some embodiments, R7 is -CH2OH. In some embodiments, R7 is 5-6 membered heteroaryl. In some embodiments, R7 is 5-membered heteroaryl. In some embodiments, R7 is thiazolyl. [0234] In some embodiments of Formula (Ib), R8, R9, and R11 are each H. In some embodiments, R8 is OH, R9 is H, and R11 is H. In some embodiments, R8 and R9 are each OH and R11 is H. In some embodiments, R8 is OH, R9 is H, and R11 is OH. In some embodiments, R8 is H, R9 is H, and R11 is OH. [0235] In some embodiments of Formula (Ib), E is a 6-membered ring. In some embodiments, E is pyridine or phenyl. In some embodiments, E is phenyl. [0236] In some embodiments of Formula (Ib), R7 is -CH2OH, R8 is H, R9 is H, and E is phenyl. [0237] In some embodiments of Formula (Ib), R7 is -CH2OH, R8 is H, and R9 is H. In some embodiments, m is 2, n is 0, X is H, R10 is methyl, R6 is isopropyl, R7 is H, R8 is OH, and R9 is OH. In some embodiments, m is 1, n is 1, X is H, R10 is methyl, R6 is isopropyl, R7 is H, R8 is OH, and R9 is OH. In some embodiments, m is 2, n is 1, X is H, R10 is methyl, R6 is isopropyl, R7 is H, R8 is OH, and R9 is OH. [0238] In some embodiments, provided is a compound of Formula (Ic):
Figure imgf000074_0001
or a salt thereof, wherein the variables are as defined for Formula (I), (Iz), or (Ia). [0239] In some embodiments, provided is a compound of Formula (Id):
Figure imgf000074_0002
or a salt thereof, wherein the variables are as defined for Formula (I), (Iz), or (Ia). [0240] In some embodiments, provided is a compound of Formula (Ie):
Figure imgf000074_0003
or a salt thereof, wherein the variables are as defined for Formula (I), (Iz), or (Ia). [0241] In some embodiments, provided is a compound of Formula (Id):
Figure imgf000075_0001
or a salt thereof, wherein the variables are as defined for Formula (I), (Iz), or (Ia). [0242] In some embodiments of Formula (Ic), (Id), (Ie), or (If), R1 and R1 are both H. R1 is H and R2 is C1-C4-alkyl. In some embodiments, R1 is H and R2 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R1 is H and R2 is ethyl or methyl. In some embodiments, R1 is H and R2 is methyl. In some embodiments, R1 and R2 are each independently C1-C4 alkyl. In some embodiments, R1 and R2 are each independently n- propyl, isopropyl, ethyl, or methyl. In some embodiments, R1 and R2 are each independently ethyl or methyl. In some embodiments, R1 and R2 are methyl. [0243] In some embodiments of Formula (Ic), (Id), (Ie), or (If), X is H, OH, -C(O)NRaRb, or -NHC(O)Ra. In some embodiments, X is H, OH, -C(O)NRaRb, or -NHC(O)Ra. In some embodiments, X is H or OH. In some embodiments, X is OH. In some embodiments, R3 is H or C1-C4 alkyl. In some embodiments, R3 is H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R3 is H, ethyl, or methyl. In some embodiments, X is H or OH and R3 is H or methyl. In some embodiments, X is OH and R3 is H. In some embodiments, X is OH and R3 is methyl. In some embodiments, Ra is ethyl or methyl. In some embodiments, Ra is methyl. [0244] In some embodiments of Formula (Ic), (Id), (Ie), or (If), R6 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R6 is ethyl or methyl. In some embodiments, R6 is isopropyl. In some embodiments, R6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R6 is isopropyl substituted with OH. In some embodiments, R6 is ethyl substituted with OH. In some embodiments, R6 is methyl substituted with OH. [0245] In some embodiments of Formula (Ic), (Id), (Ie), or (If), R7 is C1-C4 alkyl substituted with OH. In some embodiments, R7 is C1-C4 alkyl subsituted by two OH moieties. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R7 is -CH2CH2OH or CH2OH. In some embodiments, R7 is -CH2OH. In some embodiments, R7is C1-C4 alkyl. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R7 is methyl. In some embodiments, R7 is 5-6 membered heteroaryl. In some embodiments, R7 is 5-membered heteroaryl. In some embodiments, R7 is thiazolyl. [0246] In some embodiments of Formula (Ic) or (Ie), R8 and R9 are H. In some embodiments, R8 is OH and R9 is H. In some embodiments, R8 and R9 are each OH. [0247] In some embodiments of Formaul (Id) or (If), R8, R9, and R11 are H. In some embodiments, R8 is OH, R9 is H, and R11 is H. In some embodiments, R8 and R9 are each OH and R11 is H. In some embodiments, R8 is OH, R9 is H, and R11 is OH. In some embodiments, R8 is H, R9 is H, and R11 is OH. [0248] In some embodiments of Formula (Ic), (Id), (Ie), or (If), X is OH, R3 is H or methyl, R1 is H or C1-C4 alkyl, R2 is C1-C4 alkyl, R6 is C1-C4 alkyl, R7 is C1-C4 alkyl optionally substituted with OH, R8 is H or C1-C4 alkyl, and R9 is H. In some embodiments, X is OH, R3 is H, R1 is H or methyl, R2 is methyl, R6 is isopropyl, R7 is CH2OH, R8 is H, and R9 is H. [0249] In some embodiments of Formula (Ic), R7 is -CH2OH, R8 is H, and R9 is H. [0250] In some embodiments, provided is a compound of Formula (IIa):
Figure imgf000076_0001
or a salt thereof, wherein the variables are as defined for Formula (II). [0251] In some embodiments of Formula (IIa), q is 0. In some embodiments, q is 1. [0252] In some embodiments of Formula (IIa), R1 is H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R1 is H, ethyl, or methyl. In some embodiments, R1 is H or methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is methyl. In some embodiments, R1 is H. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0. [0253] In some embodiments or Formula (IIa), R6 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R6 is ethyl or methyl. In some embodiments, R6 is isopropyl. In some embodiments, R6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R6 is isopropyl substituted with OH. In some embodiments, R6 is ethyl substituted with OH. In some embodiments, R6 is methyl substituted with OH. [0254] In some embodiments of Formula (IIa), R7 is C1-C4 alkyl substituted with OH. In some embodiments, R7 is C1-C4 alkyl subsituted by two OH moieties. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R7is C1-C4 alkyl. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R7 is methyl. In some embodiments, R7 is -CH2CH2OH or CH2OH. In some embodiments, R7 is -CH2OH. In some embodiments, R7 is 5-6 membered heteroaryl. In some embodiments, R7 is 5-membered heteroaryl. In some embodiments, R7 is thiazolyl. [0255] In some embodiments of Formula (IIa), R8, R9, and R11 are H. In some embodiments, R8 is OH, R9 is H, and R11 is H. In some embodiments, R8 and R9 are each OH and R11 is H. In some embodiments, R8 is OH, R9 is H, and R11 is OH. In some embodiments, R8 is H, R9 is H, and R11 is OH. [0256] In some embodiments of Formula (IIa), E is a 6-membered ring. In some embodiments, E is pyridine or phenyl. In some embodiments, E is phenyl. [0257] In some embodiments of Formula (IIa), R7 is -CH2OH, R8 is H, R9 is H, and R11 is H. [0258] In some embodiments, provided is a compound of Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt). Table 1. Hydrophilic auristatin compounds
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Drug-Linker Compounds [0259] In some embodiments, when preparing Ligand-Drug Conjugate compounds described herein, it will be desirable to synthesize the full Drug-Linker compound prior to conjugation to a targeting agent, which becomes the Ligand Unit of the Ligand-Drug conjugate compound. In such embodiments, Drug-Linker compounds as described herein, are intermediate compounds. In those embodiments, the Stretcher Unit in a Drug-Linker compound is not yet covalently attached to the Ligand Unit (i.e., is a Stretcher Unit precursor, Z'), and therefore has a functional group for conjugation to a targeting agent. In one embodiment, a Drug-Linker compound comprises an auristatin moiety (shown herein as Formulae (I) and (II), or any subformula thereof) or, and a Linker Unit (Q) through which the Ligand Unit is connected to the Drug Unit. [0260] In another embodiment, a Drug-Linker compound comprises an auristatin compound of Formula (I), or any subformula thereof, as a Drug Unit and a Linker Unit (Q) comprising a Releasable Linker (RL) that is other than a Glycoside (e.g., Glucuronide) Unit through which the Ligand Unit is connected to the conjugated auristatin compound. The Linker Unit comprises, in addition to RL, a Stretcher Unit precursor (Z') comprising a functional group for conjugation to a targeting agent that is the precursor to the Ligand Unit and thus is capable of (directly or indirectly) connecting the RL to the Ligand Unit. In some of those embodiments a Parallel Connector Unit (B) is present when it is desired to add a Partitioning Agent (S*) as a side chain appendage. In any one of those embodiments, a Connector Unit (A) is present when it is desirable to add more distance between the Stretcher Unit and RL. [0261] In one group of embodiments, a Drug-Linker compound comprises an auristatin compound of Formula (I), or any subformula thereof, and a Linker Unit (Q), wherein Q comprises a Releasable Linker (RL) that is a Glycoside (e.g., Glucuronide) Unit, directly attached to a Stretcher Unit precursor (Z') or indirectly to Z' through attachment to intervening component(s) of the Drug-Linker compound’s Linker Unit (i.e., A, S* and/or B(S*)), wherein Z' comprises a functional group capable of forming a covalent bond to a targeting agent. [0262] In another group of embodiments, a Drug-Linker compound comprises an auristatin of Formula (I), or any subformula thereof, and a Linker Unit (Q), wherein Q comprises a Releasable Linker (RL) that is other than a Glycoside (e.g., Glucuronide) Unit (RL), directly attached to a Stretcher Unit precursor (Z') or indirectly to Z' through attachment to intervening component(s) of the Drug-Linker compound’s Linker Unit (i.e., A, S* and/or B(S*)), wherein Z' comprises a functional group capable of forming a covalent bond to a targeting agent. [0263] In some embodiments, the Drug-Linker compound has the formula: Q-D, or a salt thereof, wherein Q is a Linker Unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S*-RL-, (iv) Z'-A-S*-RL-Y-, (v) Z'-A-B(S*)-RL-, (vi) Z'-A-B(S*)-RL-Y-, (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-; Z' is a Stretcher Unit precursor; A is a bond or a Connector Unit; B is a Parallel Connector Unit; S* is a Partitioning Agent; RL is a Releasable Linker; W is a Amino Acid Unit; Y is a Spacer Unit; and D is a Drug Unit of Formula (I'):
Figure imgf000088_0001
(I') wherein Xb is -NR2-# or -N+R1R5-#, wherein the # denotes the point of attachment to Q, and Xa
Figure imgf000088_0002
Xa and Xb are taken together with the carbon atom to which they are attached to form
Figure imgf000089_0001
, wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups, and the # denotes the point of attachment to Q; R1 and R5 are independently C1-C4 alkyl; X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R2, R3, R4, R10, Ra, and Rb are each independently H or C1-C4 alkyl; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1; and wherein when X is H, at least two of R7, R8, R9, and R11 comprise an OH moiety. [0264] In the context of the Drug-Linker Compounds – the assembly is best described in terms of its component groups. While some procedures for the preparation of Drug-Linker compounds are described herein, the order of assembly and the general conditions to prepare the compounds will be well understood by one of skill in the art in view of the teachings of the application. Component groups 1. Drug Unit D [0265] The Drug Units of the Drug-Linker compounds, or Ligand-Drug Conjugate thereof, provided herein are auristatin moieities of the compounds disclosed herein and are referred to herein as Drug Units. [0266] In some embodiments, the Drug Unit D has Formula (I'), as described above. [0267] In some embodiments of Formula (I'), q is 0. In some embodiments, q is 1. [0268] In some embodiments, the Drug Unit D has Formula (Iz'):
Figure imgf000090_0001
wherein Xb is -NR2-# or -N+R1R5-#, wherein the # denotes the point of attachment to Q, and Xa ken together with the carbon atom to which they are attached to form
Figure imgf000090_0002
wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups, and the # denotes the point of attachment to Q; R1 and R5 are independently C1-C4 alkyl; X is OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or - NHC(O)Ra; R2, R3, R4, R10, Ra, and Rb are each independently H or C1-C4 alkyl; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; and q is 0 or 1. [0269] In some embodiments of Formula (I') or (Iz'), q is 0. In some embodiments, q is 1. [0270] In some embodiments, of Formula (I') or (Iz'), Xb is -NR2-# or -N+R1R5-#, wherein the # denotes the point of attachment to Q, and Xa is
Figure imgf000090_0003
. In some embodiments, R1 and R2 are each independently C1-C4 alkyl. In some embodiments, R1 and R5 are each independently n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R1 and R5 are each independently ethyl or methyl. In some embodiments, R1 and R5 are methyl. In some emodiments, R3 and R4 are each independently C1-C4 alkyl. In some embodiments, R3 is H and R4 is C1-C4 alkyl. In some embodiments, R3 and R4 are H. In some embodiments, R3 is H and R4 is methyl. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 0. In some embodiments, R1 is methyl, R5 is methyl, R3 is H, R4 is H, and n is 0. In some embodiments, R2 is n-propyl, isopropyl, ethyl or methyl. In some embodiments, R2 is ethyl or methyl. In some embodiments, R2 is methyl. In some embodiments, R2 is H. [0271] In some embodiments of Formula (I') or (Iz'), Xa and Xb are taken together with the carbon atom to which they are attached to form
Figure imgf000091_0001
, wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups, and the # denotes the point of attachment to Q. In some embodiments, R5 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R5 is ethyl or methyl. In some embodiments, R5 is ethyl. In some embodiments, R5 is methyl. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 2 or 3. In some embodiments, m is 2. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, m is 1 or 2 and n is 0 or 1. [0272] In some embodiments of Formula (I'), X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra, -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH, -S(O)2Ra, -S(O)-Ra, -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is H or OH. In some embodiments, X is OH. In some embodiments, X is OH, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is H, OH, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is H, OH, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is H, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is H, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is H, OH, or -C(O)NRaRb. In some embodiments, X is OH or -C(O)NRaRb. In some embodiments, X is H or -C(O)NRaRb. In some embodiments, Ra and Rb are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra and Rb are independently H, ethyl, or methyl. In some embodiments, Ra and Rb are independently H or methyl. In some embodiments, Ra is H and Rb is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra is H and Rb is methyl. [0273] In some embodiments of Formula (Iz'), X is OH, -C(O)NRaRb, -S(O)2Ra, -S(O)- Ra, -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH. In some embodiments, X is OH, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is OH or -C(O)NRaRb. In some embodiments, X is -C(O)NRaRb. In some embodiments, Ra and Rb are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra and Rb are independently H, ethyl, or methyl. In some embodiments, Ra and Rb are independently H or methyl. In some embodiments, Ra is H and Rb is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra is H and Rb is methyl. [0274] In some embodiments of Formula (I') or (Iz'), Xb is-N+R1R5-# and Xa is X is OH, R1 is methyl or methyl, R5 is methyl, R3 is H, R4 is H, and n is 0. In
Figure imgf000092_0001
some embodiments, X is OH, R1 is methyl, R5 is methyl, R3 is H, R4 is H, and n is 0. In some embodiments, X is OH, R3 and R4 are H, and n is 0. [0275] In some embodiments of Formula (I') or (Iz'), Xb is -NR2-#, Xa is
Figure imgf000092_0002
, X is OH, and R2 is H or C1-C4 alkyl. In some embodiments, Xb is -NR2-# and Xa is X
Figure imgf000092_0003
is OH, and R2 is H. In some embodiments, Xb is -NR2-# and Xa is
Figure imgf000092_0004
X is OH, and R2 is C1-C4 alkyl. [0276] In some embodiments or Formula (I') or (Iz'), R6 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R6 is ethyl or methyl. In some embodiments, R6 is isopropyl. In some embodiments, R6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R6 is isopropyl substituted with OH. In some embodiments, R6 is ethyl substituted with OH. In some embodiments, R6 is methyl substituted with OH. [0277] In some embodiments of Formula (I') or (Iz'), R7 is C1-C4 alkyl substituted with OH. In some embodiments, R7 is C1-C4 alkyl substituted by two OH moieties. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R7is C1-C4 alkyl. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R7 is methyl. In some embodiments, R7 is -CH2CH2OH or CH2OH. In some embodiments, R7 is -CH2OH. In some embodiments, R7 is 5-6 membered heteroaryl. In some embodiments, R7 is 5-membered heteroaryl. In some embodiments, R7 is thiazolyl. [0278] In some embodiments of Formula (I') or (Iz'), R8, R9, and R11 are H. In some embodiments, R8 is OH, R9 is H, and R11 is H. In some embodiments, R8 and R9 are each OH and R11 is H. In some embodiments, R8 is OH, R9 is H, and R11 is OH. In some embodiments, R8 is H, R9 is H, and R11 is OH. [0279] In some embodiments of Formula (I') or (Iz'), E is an optionally substituted 6- membered ring. In some embodiments, E is pyridine or phenyl, each of which is optionally substituted. In some embodiments, E is optionally substituted phenyl. In some embodiments, E is optionally substituted 5-6 membered heteroaryl. In some embodiments, E is optionally substituted 5-membered heteroaryl. In some embodiments, E is pyridine or phenyl, each of which is unsubstituted. In some embodiments, E is unsubstituted phenyl. In some embodiments, E is unsubstituted 5-6 membered heteroaryl. In some embodiments, E is unsubstituted 5-membered heteroaryl. [0280] In some embodiments of Formula (I') or (Iz'), R7 is -CH2OH, R8 is H, R9 is H, and E is phenyl. [0281] In some embodiments, the Drug Unit D has Formula (Ia') or (Ia''):
Figure imgf000093_0001
or a salt thereof, wherein R1 and R5 are independently C1-C4 alkyl; X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R2, R3, Ra, and Rb are each independently H or C1-C4 alkyl; R6 is C1-C4 alkyl; R7 is H, C1-C4 alkyl optionally substituted with OH, or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; q is 0 or 1; and the wavy line is the site of attachment to the rest of the Drug-Linker compound. [0282] In some embodiments of Formula (Ia') and (Ia''), q is 0. In some embodiments, q is 1. [0283] In some embodiments of Formula (Ia'), R2 is C1-C4-alkyl. In some embodiments, R2 is n-propyl, isopropyl, ethyl, or methyl. R2 is ethyl or methyl. R2 is methyl. In some embodiments, R2 is H. In some embodiments, R2 is ethyl, methyl, or H. In some embodiments, R2 is methyl or H. [0284] In some embodiments of Formula (Ia''), R1 and R5 are each independently n- propyl, isopropyl, ethyl, or methyl. In some embodiments, R1 and R5 are each independently ethyl or methyl. In some embodiments, R1 and R5 are each methyl. In some embodiments, R1 is methyl and R5 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R1 is methyl and R5 is ethyl or methyl. In some embodiments, R1 and R5 are methyl. [0285] In some embodiments of Formula (Ia') and (Ia''), X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra, -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH, -S(O)2Ra, -S(O)-Ra, -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is H or OH. In some embodiments, X is OH. In some embodiments, X is OH, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is OH, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is H, OH, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is H, OH, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is H, -NHS(O)2Ra, or -NHC(O)Ra. In some embodiments, X is H, -S(O)2Ra, -S(O)-Ra, or -S(O)2NRaRb. In some embodiments, X is H, OH, or -C(O)NRaRb. In some embodiments, X is OH or -C(O)NRaRb. In some embodiments, X is H or -C(O)NRaRb. In some embodiments, Ra and Rb are independently H, n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra and Rb are independently H, ethyl, or methyl. In some embodiments, Ra and Rb are independently H or methyl. In some embodiments, Ra is H and Rb is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, Ra is H and Rb is methyl. [0286] In some embodiments of Formula (Ia') and (Ia''), R3 is H or methyl. In some embodiments, R3 is H. In some embodiments, R3 is methyl. [0287] In some embodiments of Formula (Ia') and (Ia''), R6 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R6 is ethyl or methyl. In some embodiments, R6 is isopropyl. In some embodiments, R6 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R6 is isopropyl substituted with OH. In some embodiments, R6 is ethyl substituted with OH. In some embodiments, R6 is methyl substituted with OH. [0288] In some embodiments of Formula (Ia') and (Ia''), R7 is C1-C4 alkyl substituted with OH. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl, each of which is substituted with OH. In some embodiments, R7 is -CH2CH2OH or CH2OH. In some embodiments, R7 is -CH2OH. In some embodiments, R7 is C1-C4 alkyl. In some embodiments, R7 is n-propyl, isopropyl, ethyl, or methyl. In some embodiments, R7 is methyl. In some embodiments, R7 is 5-6 membered heteroaryl. In some embodiments, R7 is 5-membered heteroaryl. In some embodiments, R7 is thiazolyl. [0289] In some embodiments of Formula (Ia') and (Ia''), R8, R9, and R11 are H. In some embodiments, R8 is OH, R9 is H, and R11 is H. In some embodiments, R8 and R9 are each OH and R11 is H. In some embodiments, R8 is OH, R9 is H, and R11 is OH. In some embodiments, R8 is H, R9 is H, and R11 is OH. [0290] In some embodiments of Formula (Ia'), X is OH, R3 is H or methyl, R2 is C1-C4 alkyl, R6 is C1-C4 alkyl, R7 is C1-C4 alkyl optionally substituted with OH, R8 is H or C1-C4 alkyl, and R9 is H. In some embodiments, q is 0, X is OH, R3 is H or methyl, R2 is C1-C4 alkyl, R6 is C1-C4 alkyl, R7 is C1-C4 alkyl optionally substituted with OH, R8 is H or C1-C4 alkyl, and R9 is H. [0291] In some embodiments of Formula (Ia''), X is OH, R3 is H or methyl, R1 C1-C4 alkyl, R5 is C1-C4 alkyl, R6 is C1-C4 alkyl, R7 is C1-C4 alkyl optionally substituted with OH, R8 is H or C1-C4 alkyl, and R9 is H. In some embodiments, q is 0, X is OH, R3 is H or methyl, R1 C1-C4 alkyl, R5 is C1-C4 alkyl, R6 is C1-C4 alkyl, R7 is C1-C4 alkyl optionally substituted with OH, R8 is H or C1-C4 alkyl, and R9 is H. [0292] In some embodiments, of the Drug Unit D has Formula (Ib') or (Ib''):
Figure imgf000096_0001
wherein the variables are as defined for Formula (Ib) and the wavy line is the site of attachment to the rest of the Drug-Linker compound. [0293] In some embodiments of Formula (Ib') and (Ib''), R7 is -CH2OH, R8 is H, and R9 is . [0294] In some embodiments, the Drug Unit D has Formula (Ic') or (Ic''):
Figure imgf000096_0002
wherein the variables are as defined for Formula (Ic) and the wavy line is the site of attachment to the rest of the Drug-Linker compound. [0295] In some embodiments of Formula (Ic') or (Ic''), X is OH and R3 is H. In some embodiments, R7 is -CH2OH, R8 is H, and R9 is H. In some embodiments, X is OH, R7 is -CH2OH, R8 is H, and R9 is H. In some embodiments, X is OH, R3 is H, R7 is -CH2OH, R8 is H, and R9 is H. [0296] In some embodiments, the Drug Unit D has the Formula (Id') or (Id''):
Figure imgf000097_0001
wherein the variables are as defined for Formula (Id) and the wavy line is the site of attachement to the rest of the Drug-Linker compound. [0297] In some embodiments, the Drug Unit D has Formula (Ie') or (Ie''):
Figure imgf000097_0002
wherein the variables are as defined for Formula (Ie) and the wavy line is the site of attachment to the rest of the Drug-Linker compound. [0298] In some embodiments, the Drug Unit D has the Formula (Id') or (Id''):
Figure imgf000097_0003
wherein the variables are as defined for Formula (If) and the wavy line is the site of attachement to the rest of the Drug-Linker compound. [0299] In some embodiments of Formula (Id'), (Id''), (If'), or (If''), X is OH and R3 is H. In some embodiments, R7 is -CH2OH, R8 is H, and R9 is H. In some embodiments, X is OH, R7 is -CH2OH, R8 is H, and R9 is H. In some embodiments, X is OH, R3 is H, R7 is -CH2OH, R8 is H, and R9 is H. [0300] In some embodiments of Formula (Ia''), (Ic''), (Id''), (Ie''), or (If'') the quaternized nitrogen atom prevents cyclization of the Drug Unit. In some embodiments, the quaternized nitrogen atom prevents premature release of the Drug Unit from the Drug-Linker compound or moiety (e.g., in a Ligand-Drug Conjugate compound). In some embodiments, the quaternized nitrogen atom prevents cyclization and premature release of the Drug Unit from the Drug-Linker compound or moiety (e.g., in a Ligand-Drug Conjugate compound). 2. Linker Unit Q [0301] As noted above, is some embodiments, the Linker Unit Q has a formula selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S*-RL-, (iv) Z'-A-S*-RL-Y-, (v) Z'-A-B(S*)-RL-, (vi) Z'-A-B(S*)-RL-Y-, (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-; wherein Z' is a Stretcher Unit; A is a bond or a Connector Unit; B is a Parallel Connector Unit; S* is a Partitioning Agent; RL is Releasable Linker; W is an Amino Acid Unit; and Y is a Spacer Unit. [0302] In other embodiments, the Linker Unit Q has a formula selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S*-RL-, (iv) Z'-A-S*-RL-Y-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-. [0303] In some embodiments, the Linker Unit Q has a formula selected from the group consisting of: (v) Z'-A-B(S*)-RL-, (vi) Z'-A-B(S*)-RL-Y-, (ix) Z'-A-B(S*)-W-, and (xi) Z'-A-B(S*)-W-RL-. [0304] In some embodiments, the Linker Unit Q has a formula selected from the group consisting of: (iii) Z'-A-S*-RL-, (iv) Z'-A-S*-RL-Y-, (v) Z'-A-B(S*)-RL-, (vi) Z'-A-B(S*)-RL-Y-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-. [0305] In some embodiments, the Linker Unit Q has a formula selected from the group consisting of: (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-. 3. Stretcher Unit Z' [0306] A Stretcher Unit (Z) is a component of a Ligand-Drug Conjugate that acts to connect the Ligand Unit to the remainder of the conjugate. A Stretcher Unit precursor (Z') is a component of a Drug-Linker compound or intermediate thereof has a functional group that can form a bond with a functional group of a targeting ligand to form a Stretcher Unit (Z). [0307] In some embodiments, a Stretcher Unit precursor (Z') has an electrophilic group that is capable of interacting with a reactive nucleophilic group present on a Ligand Unit (e.g., an antibody) to provide a covalent bond between a Ligand Unit and the Stretcher Unit of a Linker Unit. Nucleophilic groups on an antibody having that capability include but are not limited to, sulfhydryl, hydroxyl and amino functional groups. In some aspects, the heteroatom of the nucleophilic group of an antibody is reactive to an electrophilic group on a Stretcher Unit precursor and can provide a covalent bond between the Ligand Unit and Stretcher Unit of a Linker Unit or Drug-Linker moiety. Useful electrophilic groups for that purpose include, but are not limited to, maleimide, haloacetamide groups, and NHS esters. The electrophilic group provides a convenient site for antibody attachment to form a Ligand- Drug Conjugate compound or Ligand Unit-Linker intermediate compound. [0308] In other embodiments, a Stretcher Unit precursor has a reactive site which has a nucleophilic group that is reactive to an electrophilic group present on a Ligand Unit (e.g., an antibody). Useful electrophilic groups on an antibody for that purpose include, but are not limited to, aldehyde and ketone carbonyl groups. The heteroatom of a nucleophilic group of a Stretcher Unit precursor can react with an electrophilic group on an antibody and form a covalent bond to the antibody. Useful nucleophilic groups on a Stretcher Unit precursor for that purpose include, but are not limited to, hydrazide, hydroxylamine, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide. The electrophilic group on an antibody provides a convenient site for antibody attachment to form a Ligand-Drug Conjugate compound or Ligand Unit-Linker intermediate compound. [0309] In some embodiments, a sulfur atom of a Ligand Unit is bound to a succinimide ring system of a Stretcher Unit formed by reaction of a thiol functional group of a targeting ligand with a maleimide moiety of the corresponding Stretcher Unit precursor. In other embodiments, a thiol functional group of a Ligand Unit reacts with an alpha haloacetamide moiety to provide a sulfur-bonded Stretcher Unit by nucleophilic displacement of its halogen substituent. [0310] Illustrative Stretcher Units prior to conjugation to the Ligand Unit (i.e., Stretcher Unit precursors) comprise a maleimide moiety and are represented by structures including that of formula Z'a
Figure imgf000101_0001
wherein the wavy line adjacent the carbonyl carbon atom indicates attachment to B, A, or S*, in the formulae above, depending on the presence or absence of A and/or B, R17 is –(CH2)1-5– or –CH2CH2(OCH2CH2)1-36–. In some embodiments, R17 is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, –CH2CH2OCH2CH2-, –CH2CH2(OCH2CH2)2–, –CH2CH2(OCH2CH2)3–, –CH2CH2(OCH2CH2)4–, –CH2CH2(OCH2CH2)5–, –CH2CH2(OCH2CH2)6–, –CH2CH2(OCH2CH2)7–, –CH2CH2(OCH2CH2)8–, –CH2CH2(OCH2CH2)10–, –CH2CH2(OCH2CH2)12–, –CH2CH2(OCH2CH2)14–, –CH2CH2(OCH2CH2)16–, –CH2CH2(OCH2CH2)18–, –CH2CH2(OCH2CH2)20–, –CH2CH2(OCH2CH2)24–, –CH2CH2(OCH2CH2)28–, –CH2CH2(OCH2CH2)32–, or –CH2CH2(OCH2CH2)36–. [0311] Other illustrative Stretcher Units prior to conjugation to the Ligand Unit (i.e., Stretcher Unit precursors) comprises a maleimide moiety and are represented by structures including that of formula Z'a-BU
Figure imgf000101_0002
wherein the wavy line adjacent the carbonyl carbon atom indicates attachment to B, A, or S*, in the formulae above, depending on the presence or absence of A and/or B, R17 is R17 is –(CH2)1-5– or –CH2CH2(OCH2CH2)1-5–, substituted with a Basic Unit (BU), such as an optionally substituted aminoalkyl, e.g., –(CH2 )xNH2, –(CH2 )xNHRa, and –(CH2 )xN(Ra) 2, wherein subscript x is an integer of from 1-4, preferably R17 is -CH2- or -CH2CH2- and subscript x is 1 or 2, and each Ra is independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or two Ra groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group. [0312] In some embodiments of formula Z'a, a Stretcher Unit precursor (Z') is represented by one of the following structures:
Figure imgf000102_0001
, wherein the wavy line adjacent to the carbonyl is as defined for Z'a or Z'a-BU. [0313] In other embodiments the Stretcher unit precursor (Z') comprises a maleimide moiety and is represented by the structure of:
Figure imgf000102_0002
, wherein the wavy line adjacent to the carbonyl is as defined for Z'a and the amino group is optional protonated or protected by an amino protecting group. [0314] In Stretcher Units having a BU moiety, it will be understood that the amino functional group of that moiety is typically protected by an amino protecting group during synthesis, e.g., an acid labile protecting group (e.g., BOC). [0315] Illustrative Stretcher Unit precursors covalently attached to a Connector Unit that comprise the structure of Z'a or Z'a-BU in which –R17- or –R17(BU)- is –CH2-, -CH2CH2- or –CH(CH2NH2)- have the following structures:
Figure imgf000103_0001
, wherein the wavy line adjacent to the carbonyl is as defined for Z'a or Z'a-BU. [0316] Other Stretcher Unit precursors bonded a Connector Unit (A) have the structures above wherein A in any one of the above Z'-A- and Z'(BU)-A- structures is replaced by a Parallel Connector Unit and Partitioning Agent (-B(S*)-) having the structure of
Figure imgf000103_0002
, wherein subscript m ranges from 1 to 6; n ranges from 8 to 24; RPEG is a PEG Capping Unit , preferably H, –CH3, or –CH2CH2CO2H, the asterisk (*) indicates covalent attachment to the Stretcher Unit precursor corresponding in structure to formula Z'a and the wavy line indicates covalent attachment to RL. In instances such as those shown here, the shown PEG group is meant to be exemplary of a variety of Partitioning Agents including PEG groups of different lengths and other Partitioning Agents that are directly attached or modified for attachment to the Parallel Connector Unit. [0317] In some aspects of the prevent invention the Stretcher Unit has a mass of no more than about 1000 daltons, no more than about 500 daltons, no more than about 200 daltons, from about 30, 50 or 100 daltons to about 1000 daltons, from about 30, 50 or 100 daltons to about 500 daltons, or from about 30, 50 or 100 daltons to about 200 daltons. 4. Connector Unit (A) [0318] In some embodiments, a Connector Unit (A), is included in a Drug-Linker Compound in instances where it is desirable to add additional distance between the Stretcher Unit precursor (Z') and the Releasable Linker. In some embodiments, the extra distance will aid with activation within RL. Accordingly, the Connector Unit (A), when present, extends the framework of the Linker Unit. In that regard, a Connector Unit (A) is covalently bonded with the Stretcher Unit (or its precursor) at one terminus and is covalently bonded to the optional Parallel Connector Unit or the Partitioning Agent (S*) at its other terminus. [0319] The skilled artisan will appreciate that the Connector Unit is any group that serves to provide for attachment of the Releasable Linker to the remainder of the Linker Unit (Q). The Connector Unit can, for example, comprise one or more (e.g., 1-10, preferably, 1, 2, 3, or 4) proteinogenic or non-proteinogenic amino acid, amino alcohol, amino aldehyde, diamino residues. In some embodiments, the Connector Unit is a single proteinogenic or non- proteinogenic amino acid, amino alcohol, amino aldehyde, or diamino residue. An exemplary amino acid capable of acting as Connector units is β-alanine. [0320] In some of those embodiments, the Connector Unit has the formula denoted below:
Figure imgf000104_0001
Figure imgf000105_0001
, wherein the wavy lines indicate attachment of the Connector Unit within the Drug-Linker Compound; and wherein R111 is independently selected from the group consisting of hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, - CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, - (CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, - (CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, - (CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3- pyridylmethyl-, 4-pyridylmethyl-,
Figure imgf000105_0002
, and each R100 is independently selected from hydrogen or -C1-C3 alkyl, preferably hydrogen or CH3; and subscript c is an independently selected integer from 1 to 10, preferably 1 to 3. [0321] A representative Connector Unit having a carbonyl group for attachment to the Partitioning Agent (S*) or to –B(S*)- is as follows:
Figure imgf000105_0003
, wherein in each instance R13 is independently selected from the group consisting of –CH2CH2(OCH2CH2)k–, -C1-C6 alkylene-, -C3-C8carbocyclo-, -arylene-, -C1-C10 heteroalkylene-, -C3-C8heterocyclo-, -C1-C10alkylene-arylene-, -arylene-C1-C10alkylene-, -C1- C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C1-C10alkylene-(C3-C8 heterocyclo)-, and -(C3-C8 heterocyclo)-C1-C10 alkylene-, wherein subscript k is an integer ranging from 1 to 36 and the subscript c is an integer ranging from 1 to 4. In some embodiments R13 is -C1-C6 alkylene and c is 1. [0322] Another representative Connector Unit having a carbonyl group for attachment to Partitioning Agent (S*) or to –B(S*)- is as follows:
Figure imgf000106_0001
, wherein R13 is –CH2CH2(OCH2CH2)k–, -C1-C6 alkylene-, -C3-C8carbocyclo-, -arylene-, -C1-C10 heteroalkylene-, -C3-C8heterocyclo-, -C1-C10alkylene-arylene-, -arylene-C1-C10alkylene-, -C1- C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C1-C10alkylene-(C3-C8 heterocyclo)-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-, wherein subscript k is an integer ranging from 1 to 36. In some embodiments R13 is -C1-C6 alkylene. [0323] A representative Connector Unit having a NH moiety that attaches to Partitioning Agent (S*) or to –B(S*)- is as follows:
Figure imgf000106_0002
, wherein in each instance, R13 is independently selected from the group consisting of –CH2CH2(OCH2CH2)k–, -C1-C6 alkylene-, -C3-C8carbocyclo-, -arylene-, -C1-C10 heteroalkylene-, -C3-C8heterocyclo-, -C1-C10alkylene-arylene-, -arylene-C1-C10alkylene-, -C1-C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C1-C10alkylene-(C3-C8 heterocyclo)-, and -(C3-C8 heterocyclo)-C1-C10 alkylene-, wherein subscript k is an integer ranging from 1 to 36 and subscript c is an integer ranging from 1 to 36. In some embodiments R13 is -C1-C6 alkylene and subscript c is 1. [0324] Another representative Connector Unit having a NH moiety that attaches to Partitioning Agent (S*) or to –B(S*)- is as follows:
Figure imgf000106_0003
, wherein R13 is –CH2CH2(OCH2CH2)k–, -C1-C6 alkylene-, -C3-C8carbocyclo-, -arylene-, -C1- C10 heteroalkylene-, -C3-C8heterocyclo-, -C1-C10alkylene-arylene-, -arylene-C1-C10alkylene-, -C1-C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C1-C10alkylene- (C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene-, –C(=O)C1-C6 alkylene- or -C1- C6 alkylene-C(=O)-C1-C6 alkylene, wherein subscript k is an integer ranging from 1 to 36. [0325] Selected embodiments of Connector Units include those having the following structure of:
Figure imgf000107_0001
, wherein the wavy line adjacent to the nitrogen indicates covalent attachment a Stretcher Unit (Z) (or its precursor Z'), and the wavy line adjacent to the carbonyl indicates covalent attachment to Partitioning Agent (S*) or to –B(S*)-; and m is an integer ranging from 1 to 6, preferably 2 to 6, more preferably 2 to 4. 5. Releasable Linker (RL) [0326] The Releasable Linker (RL) is capable of linking to the Spacer Unit (Y) or the Drug Unit (D). RL comprises a cleavable bond (i.e., a reactive site) that upon action by an enzyme present within a hyper-proliferating cell or hyper-activated immune cells or characteristic of the immediate environment of these abnormal or unwanted cells, or upon non-enzymatic action due to conditions more likely experienced by hyper-proliferating cells in comparison to normal cells, releases free drug. Alternatively, RL comprises a cleavable bond that is more likely acted upon intracellularly in a hyper-proliferating cell or hyper- activated immune cell due to preferential entry into such cells in comparison to normal cells. Peptide Releasable Linkers [0327] In some embodiments, the Releasable Linker is a Peptide Releasable Linker. In some embodiments, the Peptide Releasable Linker (RL) will comprise one or more contiguous or non-contiguous sequences of amino acids (e.g., so that RL has 1 to no more than 12 amino acids). The Peptide Releasable Linker can comprise or consist of, for example, an amino acid, a dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit. In some aspects, in the presence of an enzyme (e.g., a tumor-associated protease), an amide linkage between the amino acids is cleaved, which ultimately leads to release of free drug. [0328] Each amino acid is proteinogenic or non-proteinogenic and/or a D- or L-isomer provided that RL comprises a cleavable bond that, when cleaved, initiates release of the Drug Unit. In some embodiments, the Peptide Releasable Linker will comprise only proteinogenic amino acids. In some aspects, the Peptide Releasable Linker will have from 1 to no more than 12 amino acids in contiguous sequence. [0329] In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, selenocysteine, ornithine, penicillamine, β-alanine, aminoalkanoic acid, aminoalkynoic acid, aminoalkanedioic acid, aminobenzoic acid, amino- heterocyclo-alkanoic acid, heterocyclo-carboxylic acid, citrulline, statine, diaminoalkanoic acid, and derivatives thereof. In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, and selenocysteine. In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, and valine. In some embodiments, each amino acid is selected from the proteinogenic or the non- proteinogenic amino acids. [0330] In another embodiment, each amino acid is independently selected from the group consisting of the following L-(proteinogenic) amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan and valine. [0331] In another embodiment, each amino acid is independently selected from the group consisting of the following D-isomers of these proteinogenic amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamic acid, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan and valine. [0332] In certain embodiments, the Peptide Releasable Linker comprises only proteinogenic amino acids. In other embodiments, the Peptide Releasable Linker comprises only non-proteinogenic amino acids. In some embodiments, the Peptide Releasable Linker comprises a proteinogenic amino acid attached to a non-proteinogenic amino acid. In some embodiments, Peptide Releasable Linker comprises a proteinogenic amino acid attached to a D-isomer of a proteinogenic amino acid. [0333] In another embodiment, each amino acid is independently selected from the group consisting of β-alanine, N-methylglycine, glycine, lysine, valine and phenylalanine. [0334] Exemplary Peptide Releasable Linkers include dipeptides or tripeptides with-Val- Lys-Gly-, -Val-Cit-, -Phe-Lys- or –Val-Ala-. [0335] Useful Peptide Releasable Linkers are designed and optimized in their selectivity for enzymatic cleavage by a particular enzyme, for example, a tumor-associated protease. In some embodiments, cleavage of a linkage is catalyzed by cathepsin B, C or D, or a plasmin protease. [0336] In some embodiments, the Peptide Releasable Linker (RL) will be represented by -(–AA-)1-12-, or (–AA-AA-)1-6 wherein AA is at each occurrence independently selected from proteinogenic or non-proteinogenic amino acids. In one aspect, AA is at each occurrence independently selected from proteinogenic amino acids. In another aspect, RL is a tripeptide having the formula: AA1-AA2- AA3, wherein AA1, AA2 and AA3 are each independently an amino acid and wherein AA1 attaches to –NH- and AA3 attaches to S*. In yet another aspect, AA3 is gly or β-ala. [0337] In some embodiments, the Peptide Releasable Linker has the formula denoted below in the square brackets, the subscript w is an integer ranging from 1 to 12; or w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; or w is 2, 3, or 4; or w is 3; or w is 4:
Figure imgf000109_0001
, wherein R19 is, in each instance, independently selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, p-hydroxybenzyl, -CH2OH, - CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, - CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, - (CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3- pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl,
Figure imgf000110_0001
. aspects, the subscript w is not 3. [0338] In some aspects, each R19 is independently hydrogen, methyl, isopropyl, isobutyl, sec-butyl, -(CH2)3NH2, or -(CH2)4NH2. In some aspects, each R19 is independently hydrogen, isopropyl, or -(CH2)4NH2. [0339] Illustrative Peptide Releasable Linkers are represented by formulae (Pa), (Pb) and (Pc):
Figure imgf000110_0002
wherein R20 and R21 are as follows: R20 R21 benzyl (CH2)4NH2; methyl (CH2)4NH2; isopropyl (CH2)4NH2; isopropyl (CH2)3NHCONH2; benzyl (CH2)3NHCONH2; isobutyl (CH2)3NHCONH2; sec-butyl (CH2)3NHCONH2; (CH2)3NHCONH2;
Figure imgf000111_0001
benzyl methyl; and benzyl (CH2)3NHC(=NH)NH2;
Figure imgf000111_0002
wherein R20, R21 and R22 are as follows: R20 R21 R22 benzyl benzyl -(CH2)4NH2 isopropyl benzyl -(CH2)4NH2 H Benzyl -(CH2)4NH2 isopropyl -(CH2)4NH2 -H
Figure imgf000111_0003
wherein R20, R21, R22 and R23 are as follows: R20 R21 R22 R23 H benzyl isobutyl H; and methyl isobutyl methyl isobutyl. [0340] In some embodiments, RL comprises a peptide selected from the group consisting of gly-gly, gly-gly-gly, gly-gly-gly-gly, val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe- lys-gly, leu-lys-gly, gly-val-lys-gly, val-lys-gly-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu- leu-gly, gly-gly-phe-gly, gly-gly-phe-gly-gly, val-gly, and val-lys-β-ala. [0341] In other embodiments, RL comprises a peptide selected from the group consisting of gly-gly-gly, gly-gly-gly-gly, val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, gly-val-lys-gly, val-lys-gly-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly, gly-gly-phe-gly, and val-lys-β-ala. [0342] In still other embodiments, RL comprises a peptide selected from the group consisting of gly-gly-gly, val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu- lys-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly and val-lys-β-ala. [0343] In yet other embodiments, RL comprises a peptide selected from the group consisting of gly-gly-gly-gly, gly-val-lys-gly, val-lys-gly-gly, and gly-gly-phe-gly. [0344] In other embodiments, RL is a peptide selected from the group consisting of val- gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly and val-lys-β-ala. [0345] In still other embodiments, RL is val-lys-gly. [0346] In still other embodiments, RL is val-lys-β-ala. [0347] In some embodiments, the Releasable Linker RL is
Figure imgf000112_0001
wherein the wavy line adjacent to the -NH- group indicates attachment to the Stretcher Unit Z' or the Connector Unit A and the wavy line adjacent to the -C(=O)- group indicates attachment to the Spacer Unit Y or the Drug Unit D. Glycoside Unit Releasable Linkers [0348] In some embodiments, the Releasable Linker is a Glycoside (e.g., Glucuronide) Unit. In such embodiments, a self-immolation cascade is activated by operation of a glycosidase on a carbohydrate moiety of the Glycoside (e.g., Glucuronide) Unit. A number of sugars are useful in the embodiments described herein. Particular carbohydrate moieties include those of Galactose, Glucose, Mannose, Xylose, Arabinose, Mannose-6-phosphate, Fucose, Rhamnose, Gulose, Allose, 6-deoxy-glucose, Lactose, Maltose, Cellobiose, Gentiobiose, Maltotriose, GlcNAc, GalNAc and maltohexaose. [0349] A Glycoside (e.g., Glucuronide) Unit typically comprises a sugar moiety (Su) linked via an oxygen glycosidic bond to a self-immolative spacer. Cleavage of the oxygen glycosidic bond initiates the self-immolation reaction sequence that result in release of free drug. In some embodiments, the self-immolation sequence is activated from cleavage by β- glucuronidase of a Glycoside (e.g., Glucuronide) Unit, which is an exemplary glycoside unit. The Glycoside (e.g., Glucuronide) Unit comprises an activation unit and a self-immolative Spacer Unit. The Glycoside (e.g., Glucuronide) Unit comprises a sugar moiety (Su) linked via an oxygen glycosidic bond to a self-immolative Spacer Unit. [0350] In some embodiments, a Glycoside (e.g., Glucuronide) Unit comprises a sugar moiety (Su) linked via an oxygen glycoside bond (-O'-) to a Self-immolative Unit (SP) of the formula:
Figure imgf000113_0001
wherein the wavy lines indicate covalent attachment to the Drug Unit or to a Spacer Unit that is attached to the Drug Unit, and to the Stretcher Unit precursor (Z'), either directly or indirectly through the Connector Unit (A) or Parallel Connector Unit (B), Partitioning Agent (S*) or combinations of the Connector Unit and Parallel Connector Unit, as the case may be. [0351] The oxygen glycosidic bond (-O'-) is typically a β-glucuronidase-cleavage site (i.e., Su is from glucuronide), such as a glycoside bond cleavable by human, lysosomal β- glucuronidase. [0352] In some embodiments, the Glycoside (e.g., Glucuronide) Unit is represented by formula Ga, Gb, or Gc:
Figure imgf000114_0001
wherein Su is a Sugar moiety, -O'- represents an oxygen glycosidic bond; R1S, R2S and R3S independently are hydrogen, a halogen, -CN,-NO2, or other electron withdrawing group, or an electron donating group; RBZ is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, a PEG unit, a cyclodextrin unit, a polyamide, a hydrophilic peptide, a polysaccharide, and a dendrimer; and wherein the wavy line indicates attachment to a Stretcher Unit precursor (Z'), either directly or indirectly through a Connector Unit or Parallel Connector Unit or Connector unit and Parallel Connector Unit); and # indicates attachment to the Drug Unit or to a Spacer (either directly or indirectly via an intervening functional group or other moiety). [0353] In some embodiments, R1S, R2S, and R3S are independently selected from hydrogen, halogen, -CN, or -NO2. In some embodiments, R1S, R2S and R3S are each hydrogen. In some embodiments, R2S is an electron withdrawing group, preferably NO2, and R1S and R3S are each hydrogen. [0354] In some such aspects the activatable self-immolative group capable of glycosidase cleavage to initiate the self-immolative reaction sequence is represented by the formula Gd:
Figure imgf000115_0001
wherein R4S is CH2OH or –CO2H, the wavy line indicates covalent attachment to a Stretcher Unit (Z) (or its precursor Z'), either directly or indirectly through a Connector Unit or Parallel Connector Unit or Connector unit and Parallel Connector Unit, and the hash mark (#) indicates covalent attachment to the methylene carbamate unit. [0355] In some embodiments wherein the activatable self-immolative moiety comprises a Glycoside (e.g., Glucuronide) Unit, it is represented by the following formula Ge:
Figure imgf000115_0002
wherein the wavy line indicates covalent attachment to a Stretcher Unit (Z) (or its precursor Z'), either directly or indirectly through a Connector Unit or Parallel Connector Unit or Connector unit and Parallel Connector Unit and the hash mark (#) indicates covalent attachment of the benzylic carbon of a Spacer or functional group attached to the Drug Unit. In some embodiments, the structure of formula Ge is attached to the Drug Unit via a quaternized tertiary amine (N+), wherein the nitrogen atom is from a tertiary amine functional group on the unconjugated Drug Unit. [0356] Another type of Releasable Linker that provides a mechanism for separation of the Drug Unit from the Ligand Unit and other components of the Linker Unit through activation of a self-immolation cascade within the Linker Unit comprises a p-aminobenzyloxycarbonyl (PAB) moiety whose phenylene component is substituted with Jm wherein the subscript m indicating the number of substituents is an integer ranging from 0-4, and each J is independently -C1-C8 alkyl, -O-(C1-C8 alkyl), -halogen, -nitro or -cyano. [0357] In some embodiments, RL is a self-immolative group capable of releasing -D without the need for a separate hydrolysis step or subsequent self-immolative event. In some embodiments, -RL- is a PAB moiety that is linked to the carbonyl of -W- via the amino nitrogen atom of the PAB group, and connected directly to -D via a carbonate group. In related embodiments, -RL- comprises a PAB moiety that is linked to the carbonyl of -A-, -S*- or –B- via the amino nitrogen atom of the PAB group, and connected directly to -D via a carbonate group. Without being bound by any particular theory or mechanism, a possible mechanism of Drug release from RL comprises a PAB moiety in which RL is attached directly to -D via a carbonate group is shown in Toki et al. (2002) J Org. Chem. 67:1866-1872. [0358] In some embodiments, RL units containing a PAB moiety are represented by the formula:
Figure imgf000116_0001
, wherein subscript m is an integer ranging from 0-4, and each J is independently -C1-C8 alkyl, -O-(C1-C8 alkyl), -halogen, -nitro or –cyano. [0359] Other examples of self-immolative groups include, but are not limited to, aromatic compounds that are electronically similar to the PAB moiety such as 2-aminoimidazol-5- methanol derivatives (Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and ortho or para- aminobenzylacetals. Other RLs undergo cyclization upon amide bond hydrolysis, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al., Chemistry Biology, 1995, 2, 223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm, et al., J. Amer. Chem. Soc., 1972, 94, 5815) and 2-aminophenylpropionic acid amides (Amsberry, et al., J. Org. Chem., 1990, 55, 5867). [0360] In one embodiment, RL is a branched bis(hydroxymethyl)styrene (BHMS) unit. [0361] In some embodiments, RL has the formula:
Figure imgf000116_0002
wherein the wavy line marked with ** indicates the site of attachment to D; and the wavy line marked with * indicates the point of attachment to additional linker components of Q. In some embodiments, a PAB-containing RL is directly attached to the Drug Unit. 6. Partitioning Agent S* [0362] The Ligand-Drug Conjugates described herein can also include a Partitioning Agent (S*). The Partitioning Agent portions are useful, for example, to mask the hydrophobicity of particular Drug Units or Linking Unit components. [0363] Representative Partitioning Agents include polyethylene glycol (PEG) units, cyclodextrin units, polyamides, hydrophilic peptides, polysaccharides and dendrimers. [0364] When the polyethylene glycol (PEG) units, cyclodextrin units, polyamides, hydrophilic peptides, polysaccharides or dendrimers are included in Q, the groups may be present as an ‘in line’ component or as a side chain or branched component. For those embodiments in which a branched version is present, the Linker Units can include a lysine residue (or Parallel Connector Unit, B) that provides simple functional conjugation of, for example, the PEG unit, to the remainder of the Linking Unit. Polyethylene Glycol (PEG) Unit [0365] When present, polydisperse PEGs, monodisperse PEGs, and discrete PEGs are used as part of the Partitioning Agents in Compounds of the present invention. Polydisperse PEGs are a heterogeneous mixture of sizes and molecular weights whereas monodisperse PEGs are typically purified from heterogeneous mixtures and are therefore provide a single chain length and molecular weight. Preferred PEG Units are discrete PEGs, compounds that are synthesized in stepwise fashion and not via a polymerization process. Discrete PEGs provide a single molecule with defined and specified chain length. [0366] The PEG Unit provided herein can comprise one or multiple polyethylene glycol chains. A polyethylene glycol chain is composed of at least two ethylene oxide (CH2CH2O) subunits. In some embodiments the polyethylene glycol chains are linked together, for example, in a linear, branched or star shaped configuration. Typically, at least one of the PEG chains is derivitized at one end for covalent attachment to an appropriate site on a component of the Linker Unit (e.g. B) or is used as an in-line (e.g., bifunctional) linking group within to covalently join two of the Linker Unit components (e.g., Z-A-S*-RL- , Z-A-S*-RL-Y- ). Exemplary attachments within the Linker Unit are by means of non-conditionally cleavable linkages or via conditionally cleavable linkages. Exemplary attachments are via amide linkage, ether linkages, ester linkages, hydrazone linkages, oxime linkages, disulfide linkages, peptide linkages or triazole linkages. In some embodiments, attachment within the Linker Unit is by means of a non-conditionally cleavable linkage. In some embodiments, attachment within the Linker Unit is not via an ester linkage, hydrazone linkage, oxime linkage, or disulfide linkage. In some embodiments, attachment within the Linker Unit is not via a hydrazone linkage. [0367] A conditionally cleavable linkage refers to a linkage that is not substantially sensitive to cleavage while circulating in the plasma but is sensitive to cleavage in an intracellular or intratumoral environment. A non-conditionally cleavable linkage is one that is not substantially sensitive to cleavage in any biological environment. Chemical hydrolysis of a hydrazone, reduction of a disulfide, and enzymatic cleavage of a peptide bond or glycosidic linkage are examples of conditionally cleavable linkages. [0368] In some embodiments, the PEG Unit is directly attached to a Parallel Connector Unit B, wherein the other terminus (or termini) of the PEG Unit is free and untethered and may take the form of a methoxy, carboxylic acid, alcohol or other suitable functional group. The methoxy, carboxylic acid, alcohol or other suitable functional group acts as a cap for the terminal PEG subunit of the PEG Unit. By untethered, it is meant that the PEG Unit will not be attached at that untethered site to a Drug Unit, to an antibody, or to another linking component. The skilled artisan will understand that the PEG Unit in addition to comprising repeating ethylene glycol subunits may also contain non-PEG material (e.g., to facilitate coupling of multiple PEG chains to each other). Non-PEG material refers to the atoms in the PEG Unit that are not part of the repeating -CH2CH2O- subunits. In some embodiments provided herein, the PEG Unit comprises two monomeric PEG chains attached to each other via non-PEG elements. In other embodiments provided herein, the PEG Unit comprises two linear PEG chains attached to a central core or Parallel Connector Unit (i.e., the PEG Unit itself is branched). [0369] There are a number of PEG attachment methods available to those skilled in the art, [see, e.g., Goodson, et al. (1990) Bio/Technology 8:343 (PEGylation of interleukin-2 at its glycosylation site after site-directed mutagenesis); EP 0401384 (coupling PEG to G-CSF); Malik, et al., (1992) Exp. Hematol. 20:1028-1035 (PEGylation of GM-CSF using tresyl chloride); PCT Pub. No. WO 90/12874 (PEGylation of erythropoietin containing a recombinantly introduced cysteine residue using a cysteine-specific mPEG derivative); U.S. Pat. No. 5,757,078 (PEGylation of EPO peptides); U.S. Pat. No. 5,672,662 (Poly(ethylene glycol) and related polymers monosubstituted with propionic or butanoic acids and functional derivatives thereof for biotechnical applications); U.S. Pat. No. 6,077,939 (PEGylation of an N-terminal .alpha.-carbon of a peptide); Veronese et al., (1985) Appl. Biochem. Biotechnol 11:141-142 (PEGylation of an N-terminal α-carbon of a peptide with PEG- nitrophenylcarbonate ("PEG-NPC") or PEG-trichlorophenylcarbonate); and Veronese (2001) Biomaterials 22:405-417 (Review article on peptide and protein PEGylation)]. [0370] For example, PEG may be covalently bound to amino acid residues via a reactive group. Reactive groups are those to which an activated PEG molecule may be bound (e.g., a free amino or carboxyl group). For example, N-terminal amino acid residues and lysine (K) residues have a free amino group; and C-terminal amino acid residues have a free carboxyl group. Thiol groups (e.g., as found on cysteine residues) can also be useful as a reactive group for attaching PEG. In addition, enzyme-assisted methods for introducing activated groups (e.g., hydrazide, aldehyde, and aromatic-amino groups) specifically at the C-terminus of a polypeptide have been described (see Schwarz, et al. (1990) Methods Enzymol. 184:160; Rose, et al. (1991) Bioconjugate Chem. 2:154; and Gaertner, et al. (1994) J. Biol. Chem. 269:7224]. [0371] In some embodiments, PEG molecules may be attached to amino groups using methoxylated PEG ("mPEG") having different reactive moieties. Non-limiting examples of such reactive moieties include succinimidyl succinate (SS), succinimidyl carbonate (SC), mPEG-imidate, para-nitrophenylcarbonate (NPC), succinimidyl propionate (SPA), and cyanuric chloride. Non-limiting examples of such mPEGs include mPEG-succinimidyl succinate (mPEG-SS), mPEG2-succinimidyl succinate (mPEG2-SS); mPEG-succinimidyl carbonate (mPEG-SC), mPEG2-succinimidyl carbonate (mPEG2-SC); mPEG-imidate, mPEG-para-nitrophenylcarbonate (mPEG-NPC), mPEG-imidate; mPEG2-para- nitrophenylcarbonate (mPEG2-NPC); mPEG-succinimidyl propionate (mPEG-SPA); mPEG2- succinimidyl propionate (mPEG2-SPA); mPEG-N-hydroxy-succinimide (mPEG-NHS); mPEG2-N-hydroxy-succinimide (mPEG2-NHS); mPEG-cyanuric chloride; mPEG2-cyanuric chloride; mPEG2-Lysinol-NPC, and mPEG2-Lys-NHS. [0372] Generally, at least one of the PEG chains that make up the PEG Unit is functionalized so that it is capable of covalent attachment to other Linker Unit components. [0373] Functionalization includes, for example, via an amine, thiol, NHS ester, maleimide, alkyne, azide, carbonyl, or other functional group. In some embodiments, the PEG Unit further comprises non-PEG material (i.e., material does not comprise -CH2CH2O-) that provides coupling to other Linker Unit components or to facilitate coupling of two or more PEG chains. [0374] The presence of the PEG Unit (or other Partitioning Agent) in the Linker Unit can have two potential impacts upon the pharmacokinetics of the resulting Ligand-Drug Conjugate. The desired impact is a decrease in clearance (and consequent increase in exposure) that arises from the reduction in non-specific interactions induced by the exposed hydrophobic elements of the Ligand-Drug Conjugate or to the Drug Unit itself. The second impact is undesired and is a decrease in volume and rate of distribution that sometimes arises from the increase in the molecular weight of the Ligand-Drug Conjugate. [0375] Increasing the number of PEG subunits increases the hydrodynamic radius of a conjugate, typically resulting in decreased diffusivity. In turn, decreased diffusivity typically diminishes the ability of the Ligand-Drug Conjugate to penetrate into a tumor (Schmidt and Wittrup, Mol Cancer Ther 2009;8:2861-2871). Because of these two competing pharmacokinetic effects, it is desirable to use a PEG that is sufficiently large to decrease the Ligand-Drug Conjugate clearance thus increasing plasma exposure, but not so large as to greatly diminish its diffusivity, to an extent that it interferes with the ability of the Ligand- Drug Conjugate to reach the intended target cell population. See the examples (e.g., examples 1, 18, and 21) of US2016/0310612, which are incorporated by reference herein, for methodology for selecting an optimal PEG size for a particular drug-linker. [0376] In one group of embodiments, the PEG Unit comprises one or more linear PEG chains each having at least 2 subunits, at least 3 subunits, at least 4 subunits, at least 5 subunits, at least 6 subunits, at least 7 subunits, at least 8 subunits, at least 9 subunits, at least 10 subunits, at least 11 subunits, at least 12 subunits, at least 13 subunits, at least 14 subunits, at least 15 subunits, at least 16 subunits, at least 17 subunits, at least 18 subunits, at least 19 subunits, at least 20 subunits, at least 21 subunits, at least 22 subunits, at least 23 subunits, or at least 24 subunits. In some embodiments, the PEG Unit comprises a combined total of at least 4 subunits, at least 6 subunits, at least 8 subunits, at least 10 subunits, or at least 12 subunits. In some such embodiments, the PEG Unit comprises no more than a combined total of about 72 subunits, preferably no more than a combined total of about 36 subunits. [0377] In one group of embodiments, the PEG Unit comprises one or more linear PEG chains each having 2 subunits, 3 subunits, 4 subunits, 5 subunits, 6 subunits, 7 subunits, 8 subunits, 9 subunits, 10 subunits, 11 subunits, 12 subunits, 13 subunits, 14 subunits, 15 subunits, 16 subunits, 17 subunits, 18 subunits, 19 subunits, 20 subunits, 21 subunits, 22 subunits, 23 subunits, or 24 subunits. In some embodiments, the PEG Unit comprises a combined total of 4 subunits, 6 subunits, 8 subunits, 10 subunits, or 12 subunits. In some such embodiments, the PEG Unit comprises no more than a combined total of about 72 subunits, preferably no more than a combined total of about 36 subunits. [0378] In another group of embodiments, the PEG Unit comprises a combined total of from 4 to 72, 4 to 60, 4 to 48, 4 to 36 or 4 to 24 subunits, from 5 to 72, 5 to 60, 5 to 48, 5 to 36 or 5 to 24 subunits, from 6 to 72, 6 to 60, 6 to 48, 6 to 36 or from 6 to 24 subunits, from 7 to 72, 7 to 60, 7 to 48, 7 to 36 or 7 to 24 subunits, from 8 to 72, 8 to 60, 8 to 48, 8 to 36 or 8 to 24 subunits, from 9 to 72, 9 to 60, 9 to 48, 9 to 36 or 9 to 24 subunits, from 10 to 72, 10 to 60, 10 to 48, 10 to 36 or 10 to 24 subunits, from 11 to 72, 11 to 60, 11 to 48, 11 to 36 or 11 to 24 subunits, from 12 to 72, 12 to 60, 12 to 48, 12 to 36 or 12 to 24 subunits, from 13 to 72, 13 to 60, 13 to 48, 13 to 36 or 13 to 24 subunits, from 14 to 72, 14 to 60, 14 to 48, 14 to 36 or 14 to 24 subunits, from 15 to 72, 15 to 60, 15 to 48, 15 to 36 or 15 to 24 subunits, from 16 to 72, 16 to 60, 16 to 48, 16 to 36 or 16 to 24 subunits, from 17 to 72, 17 to 60, 17 to 48, 17 to 36 or 17 to 24 subunits, from 18 to 72, 18 to 60, 18 to 48, 18 to 36 or 18 to 24 subunits, from 19 to 72, 19 to 60, 19 to 48, 19 to 36 or 19 to 24 subunits, from 20 to 72, 20 to 60, 20 to 48, 20 to 36 or 20 to 24 subunits, from 21 to 72, 21 to 60, 21 to 48, 21 to 36 or 21 to 24 subunits, from 22 to 72, 22 to 60, 22 to 48, 22 to 36 or 22 to 24 subunits, from 23 to 72, 23 to 60, 23 to 48, 23 to 36 or 23 to 24 subunits, or from 24 to 72, 24 to 60, 24 to 48, 24 to 36 or 24 subunits. [0379] In some embodiments, the Partitioning Agent S* is a linear PEG Unit comprising from 2 to 20, or from 2 to 12, or from 4 to 12, or 4, 8, or 12 -CH2CH2O- subunits. In some embodiments, the linear PEG Unit is connected at one end of the PEG Unit to the RL Unit and at the other end of the PEG Unit to the Stretcher/Connector Units (Z-A-). In some embodiments, the PEG Unit is connected to the RL Unit via a -CH2CH2C(O)- group that forms an amide bond with the RL Unit (e.g., -(CH2CH2O)n-CH2CH2C(O)-RL) and to the Stretcher Unit/Connector Unit (Z-A-) via an -NH- group (e.g., Z-A-NH-(CH2CH2O)n-) that forms an amide bond with the Z-A- portion. [0380] Illustrative embodiments for PEG Units that are connected to the RL and Stretcher/Connector Units (Z-A-) are shown below:
Figure imgf000122_0001
, and in a particular embodiment, the PEG Unit is:
Figure imgf000122_0002
, wherein the wavy line on the left indicates the site of attachment to Z-A-, the wavy line on the right indicates the site of attachment to RL, and each b is independently selected from 2 to 72, 4 to 72, 6 to 72, 8 to 72, 10 to 72, 12 to 72, 2 to 24, 4 to 24, 6 to 24, or 8 to 24, 2 to 12, 4 to 12, 6 to 12, and 8 to 12. In some embodiments, subscript b is 2, 4, 8, 12, or 24. In some embodiments, subscript b is 2. In some embodiments, subscript b is 4. In some embodiments, subscript b is 8. In some embodiments, subscript b is 12. [0381] In some embodiments, the linear PEG Unit that is connected to the Parallel Connector Unit at one end and comprises a terminal cap at the other end. In some embodiments, the PEG Unit is connected to the Parallel Connector Unit via a carbonyl group that forms an amide bond with the Parallel Connector Unit lysine residue amino group (e.g., – CH2CH2(OCH2CH2)k–C(O)-B-, wherein k is an integer from 1 to 36) and includes a PEG Unit terminal cap group selected from the group consisting of C1-4alkyl and C1-4alkyl-CO2H. In some embodiments, the Partitioning Agent S* is a linear PEG Unit comprising 4, 8, or 12 - CH2CH2O- subunits and a terminal methyl cap. [0382] Illustrative linear PEG Units that are used in any of the embodiments provided herein are as follows:
Figure imgf000122_0003
and in a particular embodiment, the PEG Unit is:
Figure imgf000123_0001
wherein the wavy line indicates site of attachment to the Parallel Connector Unit (B), and each n is independently selected from 4 to 72, 6 to 72, 8 to 72, 10 to 72, 12 to 72, 6 to 24, or 8 to 24. In some embodiments, subscript b is about 4, about 8, about 12, or about 24. [0383] As used to herein, terms “PEG2”, “PEG4”, “PEG8”, and “PEG12” refers to specific embodiments of PEG Unit which comprises the number of PEG subunits (i.e., the number of subscription “b”). For example, “PEG2” refers to embodiments of PEG Unit that comprises 2 PEG subunits, “PEG4” refers to embodiments of PEG Unit that comprises 4 PEG subunits, “PEG8” refers to embodiments of PEG Unit that comprises 8 PEG subunits, and “PEG12” refers to embodiments of PEG Unit that comprises 12 PEG subunits. [0384] As described herein, the PEG unit is selected such that it improves clearance of the resultant Ligand-Drug Conjugate but does not significantly impact the ability of the Conjugate to penetrate into the tumor. In embodiments, the PEG unit to be selected for use will preferably have from 2 subunits to about 24 subunits, from 4 subunits to about 24 subunits, more preferably about 4 subunits to about 12 subunits. [0385] In some embodiments of the present disclosure the PEG Unit is from about 300 daltons to about 5 kilodaltons; from about 300 daltons, to about 4 kilodaltons; from about 300 daltons, to about 3 kilodaltons; from about 300 daltons, to about 2 kilodaltons; or from about 300 daltons, to about 1 kilodalton. In some such aspects, the PEG Unit has at least 6 subunits or at least 8, 10 or 12 subunits. In some such aspects, the PEG Unit has at least 6 subunits or at least 8, 10 or 12 subunits but no more than 72 subunits, preferably no more than 36 subunits. [0386] It will be appreciated that when referring to PEG subunits, and depending on context, the number of subunits can represent an average number, e.g., when referring to a population of Ligand-Drug Conjugates or Drug-Linker Compounds, and/or using polydisperse PEGs. 7. Parallel Connector Unit (B) [0387] In some embodiments, the Ligand-Drug Conjugates and Drug-Linker Compounds will comprise a Parallel Connector Unit to provide a point of attachment to a Partitioning Agent (shown in the Linker Units as -B(S*)-). In some embodiments, the PEG Unit is attached to a Parallel Connector Unit such as lysine as shown below wherein the wavy line and asterisks indicate covalent linkage within the Linker Unit of a Ligand-Drug Conjugate or Drug-Linker Compound:
Figure imgf000124_0001
. [0388] In some embodiments, the Parallel Connector Unit (B) and Partitioning Agent (S*) (together, -B(S*)-) have the structure of
Figure imgf000124_0002
wherein m ranges from 0 to 6; n ranges from 2 to 24; RPEG is a PEG Capping Unit, preferably H, –CH3, or –CH2CH2CO2H, the asterisk (*) indicates covalent attachment to a Connector Unit A corresponding in formula Za, Za', Zb' or Zc' and the wavy line indicates covalent attachment to the Releasable Linker (RL). In some embodiments, the structure is attached to a Connector Unit A in formula Za or Za’. In some embodiments, n is 2, 4, 8, or 12. In instances such as those shown here, the shown PEG group is meant to be exemplary of a variety of Partitioning Agents including PEG groups of different lengths and other Partitioning Agents that are directly attached or modified for attachment to the Parallel Connector Unit. 8. Spacer Unit (Y) [0389] In some embodiments, the Ligand-Drug Conjugates provided herein will have a Spacer (Y) between the Releasable Linker (RL) and the Drug Unit. The Spacer Unit is a functional group to facilitate attachment of RL to the Drug Unit, or provides additional structural components to further facilitate release of the Drug Unit from the remainder of the Conjugate (e.g., a methylene carbamate unit or a self-immolative para-aminobenzyl (PAB) component). [0390] In those embodiments to further facilitate release of the Drug Unit as free drug, the Spacer Unit Y is represented by one of the following formulae:
Figure imgf000125_0004
wherein EWG represents an electron-withdrawing group and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof. In some embodiments, EWG is selected from the group consisting of -CN, -NO2, -CX3, -X, -C(=O)OR', - C(=O)N(R')2, -C(=O)R', -C(=O)X, -S(=O)2R', -S(=O)2OR', -S(=O)2NHR', -S(=O)2N(R')2, - P(=O)(OR')2, -P(=O)(CH3)NHR', -NO, -N(R')3 +, wherein X is -F, -Br, -Cl, or -I, and R' is independently selected from the group consisting of hydrogen and C1-C6 alkyl. [0391] In some embodiments, the Spacer Unit-Drug Unit group (–Y-T*-D) is represented by one of the following formulae:
Figure imgf000125_0003
wherein the wavy line adjacent is the point of covalent attachment to RL, T* is as defined above, and D' represents the remainder of the Drug Unit, wherein T* and D' together form a Drug Unit of Formula (Ia), or any subformula thereof. [0392] In some embodiments, the Spacer Unit is represented by the formula:
Figure imgf000125_0002
wherein the wavy line adjacent to the nitrogen atom is the point of covalent attachment to RL, as defined above, and the wavy line next to the benzylic carbon atom connects to a Drug Unit. In some embodiments, the Drug Unit is attached to the benzylic carbon atom via a quaternized tertiary amine (N+) of D. [0393] In still other embodiments, the Spacer Unit is represented by the formula:
Figure imgf000125_0001
wherein the wavy line adjacent to the nitrogen atom is the point of covalent attachment to RL, as defined above, and the wavy line next to the -OC(O)- group connects to a Drug Unit. In some embodiments, the Drug Unit is attached via a primary or secondary amine. [0394] In some embodiments, provided herein is a Drug-Linker compound of Table 2, or a salt thereof. Table 2. Drug-Linker compounds
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Ligand-Drug Conjugate compounds [0395] In context of Ligand-Drug Conjugate compounds – the assembly is described by the component groups as described for Drug-Linker compounds, with the exception of the Stretcher Unit Z and the Ligand Unit L. The Stretcher Unit Z is coordinated to the Ligand Unit L in Ligand-Drug Conjugate compounds, as described below. While some procedures for the preparation of Ligand-Drug Conjugate compounds are described herein, the order of assembly and the general conditions to prepare the compounds will be well understood by one of skill in the art. [0396] In some embodiments, a Ligand-Drug Conjugate compound comprises an auristatin compound of Formula (I), or any subformula thereof, a Linker Unit (Q) comprising a Releasable Linker (RL) that is other than a Glycoside (e.g., Glucuronide) Unit through which the Ligand Unit is connected to the conjugated auristatin compound, and a Ligand Unit (L). The Linker Unit comprises, in addition to RL, a Stretcher Unit (Z) connected to the Ligand Unit and is capable of (directly or indirectly) connecting the RL to the Ligand Unit. In some embodiments, a Parallel Connector Unit (B) is present when it is desired to add a Partitioning Agent (S*) as a side chain appendage. In any one of those embodiments, a Connector Unit (A) is present when it is desirable to add more distance between the Stretcher Unit and RL. [0397] In some embodiments, a Ligand-Drug Conjugate compound comprises an auristatin compound of Formula (I), or any subformula thereof, and a Linker Unit (Q), wherein Q comprises a Releasable Linker (RL) that is a Glycoside (e.g., Glucuronide) Unit, directly attached to a Stretcher Unit (Z) or indirectly to Z through attachment to intervening component(s) of the Ligand-Drug Conjugate compound’s Linker Unit (i.e., A, S* and/or B(S*)), wherein Z forms a covalent bond to a targeting agent (e.g., a Ligand Unit). [0398] In another group of embodiments, a Ligand-Drug Conjugate compound comprises an auristatin of Formula (I), or any subformula thereof, a Linker Unit (Q), wherein Q comprises a Releasable Linker (RL) that is other than a Glycoside (e.g., Glucuronide) Unit (RL), directly attached to a Stretcher Unit (Z) or indirectly to Z through attachment to intervening component(s) of the Ligand-Drug Conjugate compound’s Linker Unit (i.e., A, S* and/or B(S*)), wherein Z forms a covalent bond to a targeting agent (e.g., a Ligand Unit). [0399] In some embodiments, the Ligand-Drug Conjugate compound has the formula: L-(Q-D)p or a pharmaceutically acceptable salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S*-RL-, (iv) Z'-A-S*-RL-Y-, (v) Z'-A-B(S*)-RL-, (vi) Z'-A-B(S*)-RL-Y-, (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-; Z' is a Stretcher Unit precursor; A is a bond or a Connector Unit; B is a Parallel Connector Unit; S* is a Partitioning Agent; RL is a Releasable Linker; W is a Amino Acid Unit; Y is a Spacer Unit; and D is a Drug Unit of Formula (I'):
Figure imgf000132_0001
wherein Xb is -NR2-# or -N+R1R5-#, wherein the # denotes the point of attachment to Q, and Xa ken together with the carbon atom to which they are attached to form
Figure imgf000132_0002
, wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups, and the # denotes the point of attachment to Q; R1 and R5 are independently C1-C4 alkyl; X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R2, R3, R4, R10, Ra, and Rb are each independently H or C1-C4 alkyl; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with OH, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1; and p is an integer ranging from 1 to 12, wherein when X is H, at least two of R7, R8, R9, and R11 comprise an OH moiety. [0400] In some embodiments, provided herein are Ligand-Drug Conjugate compounds of formula L-(Q-D)p, wherein the Drug Unit D has Formula (Iz*):
Figure imgf000133_0001
wherein Xb is -NR2-# or -N+R1R5-#, wherein the # denotes the point of attachment to Q, and Xa is
Figure imgf000133_0002
or Xa and Xb are taken together with the carbon atom to which they are attached to form
Figure imgf000133_0003
wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups, and the # denotes the point of attachment to Q; R1 and R5 are independently C1-C4 alkyl; X is OH, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R2, R3, R4, R10, Ra, and Rb are each independently H or C1-C4 alkyl; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with OH, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1; and p is an integer ranging from 1 to 12. [0401] In some embodiments, the Ligand-Drug Conjugate compound has Formula (Ia*) or (Ia**):
Figure imgf000134_0001
or a salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit as described above; p is an integer ranging from 1 to 12; and the remaining variables are as described for Drug-Linker moieties of Formula (Ia') or Formula (Ia'') above. [0402] In some embodiments, the Ligand-Drug Conjugate compound has Formula (Ib*) or (Ib**):
Figure imgf000134_0002
or a salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit as described above; p is an integer ranging from 1 to 12; and the remaining variables are as described for Drug-Linker moieties of Formula (Ib') or Formula (Ib'') above. [0403] In some embodiments, the Ligand-Drug Conjugate compound has Formula (Ic*) or (Ic**):
Figure imgf000135_0001
or a salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit as described above; p is an integer ranging from 1 to 12; and the remaining variables are as described for Drug-Linker moieties of Formula (Ic') or Formula (Ic'') above. [0404] In some embodiments, the Ligand-Drug Conjugate compound has Formula (Id*) or (Id**):
Figure imgf000135_0002
Figure imgf000136_0001
or a salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit as described above; p is an integer ranging from 1 to 12; and the remaining variables are as described for Drug-Linker moieties of Formula (Id') or Formula (Id'') above. [0405] In some embodiments, the Ligand-Drug Conjugate compound has Formula (Ie*) or (Ie**):
Figure imgf000136_0002
or a salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit as described above; p is an integer ranging from 1 to 12; and the remaining variables are as described for Drug-Linker moieties of Formula (Ie') or Formula (Ie'') above. [0406] In some embodiments, the Ligand-Drug Conjugate compound has Formula (If*) or (If**):
Figure imgf000137_0001
or a salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit as described above; p is an integer ranging from 1 to 12; and the remaining variables are as described for Drug-Linker moieties of Formula (If') or Formula (If'') above. [0407] In the context of the Ligand-Drug Conjugate compounds – the assembly is best described in terms of its component groups. While some procedures for the preparation of Ligand-Drug Conjugate compounds are described herein, the order of assembly and the general conditions to prepare the compounds will be well understood by one of skill in the art. The component groups of the Ligand-Drug Conjugate compounds described are in many cases identical to the component groups for Drug-Linker compounds as described above, including A, B, S*, RL, W, Y, and D. It is to be understood that embodiments are contemplated wherein the Drug Unit D of the Ligand-Drug Conjugates described herein is conforms to the description of Formula (I'), or any subformula thereof. Other component groups are described below. Stretcher Unit Z [0408] Representative Stretcher Units of such embodiments include those having the structures of:
Figure imgf000138_0001
, wherein the wavy line adjacent to R17 indicates attachment to the Parallel Connector Unit (B) or Connector Unit (A) if B is absent, or a Partitioning Agent (S*), if B is absent, the other wavy line indicates covalent attachment to a sulfur atom of a Ligand Unit, and R17 is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O- (C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3-C8 heterocyclo-, - C1-C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene-, -C1-C10 alkylene-C(=O)-, C1-C10 heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8 heterocyclo)-C(=O)-, - (C3-C8 heterocyclo)-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-NH-, -C1-C10 heteroalkylene- NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene- arylene-NH-, -arylene-C1-C10 alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, -(C3- C8 carbocyclo)-C1-C10 alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, -C3-C8 carbocyclo-S -, -O-(C1-C8 alkylene)-S -, -arylene-S-, -C1-C10 alkylene-arylene-S-, -arylene-C1-C10 alkylene-S-, -C1-C10 alkylene-(C3-C8 carbocyclo)-S-, - (C3-C8 carbocyclo)-C1-C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-, wherein subscript k is an integer ranging from 1 to 36. [0409] In some embodiments, the R17 group is optionally substituted by a Basic Unit (BU) such as an aminoalkyl moiety, e.g. –(CH2 )xNH2, –(CH2 )xNHRa, and –(CH2 )xNRa 2, wherein subscript x is an integer of from 1-4 and each Ra is independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or two Ra groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group. [0410] An illustrative Stretcher Unit is that of Formula Za or Za-BU in which R17 is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-C(=O)-, -C1-C10 heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene- C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3- C8 carbocyclo)-C1-C10 alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8 heterocyclo)-C(=O)-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-C(=O), wherein subscript k is an integer ranging from 1 to 36:
Figure imgf000139_0001
wherein the wavy line adjacent the carbonyl carbon atom indicates attachment to LP, B, A, or S*, in the formulae above, depending on the presence or absence of A and/or B, and the other wavy line indicates covalent bonding of the succinimide ring carbon atom to a sulfur atom of a Ligand Unit. In some aspects, the basic amino functional group of the Basic Unit (BU) is protected by a protecting group during synthesis. [0411] In some embodiments, Stretcher Units of formula Za and Za-BU are as follows:
Figure imgf000140_0001
Figure imgf000141_0001
wherein the wavy line adjacent the carbonyl carbon atom indicates attachment to B, A, or S*, in the formulae above, depending on the presence or absence of A and/or B, and the other wavy line indicates covalent bonding of the succinimide ring carbon atom to a sulfur atom of a Ligand Unit. [0412] It will be understood that a Ligand Unit-substituted succinimide may exist in hydrolyzed form(s). Those forms are exemplified below for hydrolysis of Za or Za-BU, wherein the structures representing the regioisomers from that hydrolysis have formula Zb and Zc or Zb-BU and Zc-BU. [0413] Accordingly, in some embodiments, a Stretcher unit (Z) comprises a succinic acid-amide moiety represented by the following:
Figure imgf000142_0001
Figure imgf000143_0001
wherein the wavy line adjacent to the carbonyl carbon atom bonded to R17 and the wavy line adjacent to the carbon atom of the succinic acid-amide moiety is as defined for Za or Za-BU, depending on the presence or absence of A and/or B; and R17 is –C1-C5 alkylene-, wherein in Zb-BU and Zc-BU the alkylene is substituted by a Basic Unit (BU), wherein BU is –(CH2 )xNH2, –(CH2)xNHRa, or –(CH2 )xN(Ra)2, wherein subscript x is an integer of from 1-4 and each Ra is independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or both Ra together with the nitrogen to which they are attached define an azetidinyl, pyrrolidinyl or piperidinyl group. [0414] In some embodiments, -Z-A- comprises a moiety derived from a maleimido- alkanoic acid moiety or an mDPR moiety. See, for example, see WO 2013/173337. In one group of embodiments, Z-A- is derived from a maleimido-propionyl moiety. [0415] In some embodiments, a Stretcher unit (Z) comprises an succinic acid-amide moiety represented by the structure of formula Zb’, Zc’, (R/S)-Zb’-BU, (S)-Zb’-BU, (R/S)- Zc'-BU or (S)-Zc’-BU as follows:
Figure imgf000143_0002
Figure imgf000144_0001
wherein the wavy lines are as defined for Za or Za-BU. [0416] In some embodiments, a Stretcher unit (Z) comprises a succinimide moiety represented by the structure of
Figure imgf000144_0002
. , which may be generated from a maleimido-amino-propionyl (mDPR) analog (a 3-amino-2- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid derivative), or comprises a succinic acid-amide moiety represented by the structure of:
Figure imgf000144_0003
. [0417] Illustrative Stretcher Units bonded to a Connector Unit (A) which comprise Za’, Zb' or Zc', in which –R17- of Za, Zb or Zc is –CH2- or -CH2CH2-, or comprise Za'-BU, Zb'- BU or Zc'-BU in which –R17(BU)- of Za'-BU, Zb'-BU or Zc'-BU is –CH(CH2NH2)-, have the following structures:
Figure imgf000144_0004
Figure imgf000145_0001
wherein the wavy lines are as defined for Za or Za-BU. [0418] Other Stretcher Units bonded to a Ligand Unit (L) and a Connector Unit (A) have the structures above wherein A in any one of the above -Za'-A-, -Za'(BU)-A-, -Za'-A-, - Za'(BU)-A-, -Zb'-A-, -Zb'(BU)-A-, -Zb'-A-, -Zb'(BU)-, -Zc'-A- and Zc'(BU)-A- structures is replaced by a Parallel Connector Unit having the structure of:
Figure imgf000146_0001
, wherein subscript m ranges from 1 to 6; n ranges from 8 to 24; RPEG is a PEG Capping Unit, preferably H, –CH3, or –CH2CH2CO2H, the asterisk (*) indicates covalent attachment to a Stretcher Unit corresponding in structure to formula Za, Za', Zb' or Zc' and the wavy line indicates covalent attachment to the Releasable Linker (RL). [0419] In another embodiment, the Stretcher Unit is attached to the Ligand Unit via a disulfide bond between a sulfur atom of the Ligand Unit and a sulfur atom of the Stretcher unit. A representative Stretcher Unit of this embodiment is depicted within the square brackets of Formula Zb:
Figure imgf000146_0002
wherein the wavy line indicates attachment to the Parallel Connector Unit (B) or Connector Unit (A) if B is absent or a Partitioning Agent (S*), if A and B are absent and R17 is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O- (C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3-C8 heterocyclo-, - C1-C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene-, -C1-C10 alkylene-C(=O)-, C1-C10 heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8 heterocyclo)-C(=O)-, - (C3-C8 heterocyclo)-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-NH-, C1-C10 heteroalkylene- NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene- arylene-NH-, -arylene-C1-C10 alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, -(C3- C8 carbocyclo)-C1-C10 alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, -C3-C8 carbocyclo-S -, -O-(C1-C8 alkylene)-S -, -arylene-S-, -C1-C10 alkylene-arylene-S-, -arylene-C1-C10 alkylene-S-, -C1-C10 alkylene-(C3-C8 carbocyclo)-S-, - (C3-C8 carbocyclo)-C1-C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-, wherein subscript k is an integer ranging from 1 to 36. [0420] In yet another embodiment, the reactive group of a Stretcher Unit precursor contains a reactive site that can form a bond with a primary or secondary amino group of a Ligand Unit. Examples of these reactive sites include, but are not limited to, activated esters such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates and isothiocyanates. Representative Stretcher Units of this embodiment are depicted within the square brackets of Formulas Zci, Zcii and Zciii:
Figure imgf000147_0001
), wherein the wavy line indicates attachment to the Parallel Connector Unit (B) or Connector Unit (A) if B is absent or a Partitioning Agent (S*), if A and B are absent and R17 is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O- (C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3-C8 heterocyclo-, - C1-C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene-, -C1-C10 alkylene-C(=O)-, C1-C10 heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8 heterocyclo)-C(=O)-, - (C3-C8 heterocyclo)-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-NH-, C1-C10 heteroalkylene- NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene- arylene-NH-, -arylene-C1-C10 alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, -(C3- C8 carbocyclo)-C1-C10 alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, -C3-C8 carbocyclo-S -, -O-(C1-C8 alkylene)-S -, -arylene-S-, -C1-C10 alkylene-arylene-S-, -arylene-C1-C10 alkylene-S-, -C1-C10 alkylene-(C3-C8 carbocyclo)-S-, - (C3-C8 carbocyclo)-C1-C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-, wherein subscript k is an integer ranging from 1 to 36. [0421] In still other embodiments, the reactive group of the Stretcher Unit precursor contains a reactive nucleophile that is capable of reacting with an electrophile present on, or introduced to, a Ligand Unit. For example, in some aspects, a carbohydrate moiety on a targeting ligand is mildly oxidized using a reagent such as sodium periodate and the resulting electrophilic functional group (-CHO) of the oxidized carbohydrate is condensed with a Stretcher Unit precursor that contains a reactive nucleophile such as a hydrazide, an oxime, a primary or secondary amine, a hydrazine, a thiosemicarbazone, a hydrazine carboxylate, or an arylhydrazide such as those described by Kaneko, T. et al. (1991) Bioconjugate Chem. 2:133-41. Representative Stretcher Units of this embodiment are depicted within the square brackets of Formulas Zdi, Zdii, and Zdiii:
Figure imgf000148_0001
diii), [0422] wherein the wavy line indicates attachment to the Parallel Connector Unit (B) or Connector Unit (A), or a Partitioning Agent (S*), if A and B are absent and R17 is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O- (C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3-C8 heterocyclo-, - C1-C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene-, -C1-C10 alkylene-C(=O)-, C1-C10 heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8 heterocyclo)-C(=O)-, - (C3-C8 heterocyclo)-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-NH-, C1-C10 heteroalkylene- NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene- arylene-NH-, -arylene-C1-C10 alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, -(C3- C8 carbocyclo)-C1-C10 alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, -C3-C8 carbocyclo-S -, -O-(C1-C8 alkylene)-S -, -arylene-S-, -C1-C10 alkylene-arylene-S-, -arylene-C1-C10 alkylene-S-, -C1-C10 alkylene-(C3-C8 carbocyclo)-S-, - (C3-C8 carbocyclo)-C1-C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-, wherein subscript k is an integer ranging from 1 to 36. [0423] In some embodiments, provided herein is a Ligand-Drug Conjguate compound of Table 3, or a pharmaceutically acceptable salt thereof. Ligand-Drug Conjugate compounds corresponding to the compounds of Table 3 but having a succinic acid-amide moiety in place of the succinimide moiety are contemplated. Table 3. Ligand-Drug Conjugate compounds
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Subscript p [0424] Subscript p represents the number of Drug Linker moieties on a Ligand Unit of an individual Ligand-Drug Conjugate compound and is an integer ranging from 1 to 16, 1 to 12, 1 to 10, or 1 to 8. In any of the embodiments herein, there are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 Drug Linker moieties conjugated to a Ligand Unit of an individual Ligand-Drug Conjugate compound. [0425] In some embodiments, any of the structures and descriptions as described herein represent a population of individual Ligand-Drug Conjugate compounds substantially identical except for the number of Drug-Linker moieties bound to each Ligand Unit (i.e., a Ligand-Drug Conjugate composition) so that subscript p represents the average number of Drug-Linker moieties bound to the Ligand Units of the Ligand-Drug Conjugate composition. In that group of embodiments, subscript p is a number ranging from 1 to about 16, 1 to about 12, 1 to about 10, or 1 to about 8, from 2 to about 16, 2 to about 12, 2 to about 10, or 2 to about 8. In some aspects, p is about 2. In some aspects, p is about 4. In some aspects, p is about 8. In some aspects, p is about 16. In some aspects, p is 2. In some aspects, p is 4. In some aspects, p is 8. In some aspects, p is 16. In some embodiments, the value of subscript p refers to the average drug loading as well as the drug loading of the predominate Ligand- Drug Conjugate compound in the composition. [0426] In some embodiments, conjugation will be via the reduced interchain disulfides and there will from 1 to about 8 Drug-Linker Compound molecules conjugated to a targeting agent that becomes a Ligand Unit. In some embodiments, conjugation will be via an introduced cysteine residue as well as reduced interchain disulfides and there will be from 1 to 10 or 1 to 12 or 1 to 14 or 1 to 16 Drug-Linker Compound moieties conjugated to a Ligand Unit. In some embodiments, conjugation will be via an introduced cysteine residue and there will be 2 or 4 Drug-Linker Compound molecules conjugated to a Ligand Unit. Ligand Unit L [0427] In some embodiments of the invention, a Ligand Unit is present. The Ligand Unit (L-) is a targeting agent that specifically binds to a target moiety. In one group of embodiments, the Ligand Unit specifically and selectively binds to a cell component (a Cell Binding Agent) or to another target molecule of interest. The Ligand Unit acts to target and present the Drug Unit (such as one of Formula (I) or any subformula thereof) to the particular target cell population with which the Ligand Unit interacts due to the presence of its targeted component or molecule and allows for subsequent release of free drug within (i.e., intracellularly) or within the vicinity of the target cells (i.e., extracellularly). Ligand Units, L, include, but are not limited to, proteins, polypeptides and peptides. Suitable Ligand Units include, for example, antibodies, e.g., full-length antibodies and antigen binding fragments thereof, interferons, lymphokines, hormones, growth factors and colony-stimulating factors, vitamins, nutrient-transport molecules (such as, but not limited to, transferrin), or any other cell binding molecule or substance. In some embodiments, the Ligand Unit (L) is from an antibody or a non-antibody protein targeting agent. [0428] In one group of embodiments a Ligand Unit is bonded to Q (a Linker Unit) which comprises a Glucuronide Releasable Linker. As noted above, in some aspects other linking components are present in the conjugates described herein to serve the purpose of providing additional space between the Drug Unit compound and the Ligand Unit (e.g., a Stretcher Unit and optionally a Connector Unit, A), or providing attributes to the composition to increases solubility (e.g., a Partitioning Agent, S*). In some of those embodiments, the Ligand Unit is bonded to Z of the Linker Unit via a heteroatom of the Ligand Unit. Heteroatoms that may be present on a Ligand Unit for that bonding include sulfur (in one embodiment, from a sulfhydryl group of a targeting ligand), oxygen (in one embodiment, from a carboxyl or hydroxyl group of a targeting ligand) and nitrogen, optionally substituted (in one embodiment, from a primary or secondary amine functional group of a targeting ligand or in another embodiment from an optionally substituted amide nitrogen). Those heteroatoms are present on the targeting ligand in the ligand’s natural state, for example in a naturally occurring antibody, or are introduced into the targeting ligand via chemical modification or biological engineering. [0429] In some embodiments, the Ligand Unit is an antibody. [0430] Useful polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of immunized animals. Useful monoclonal antibodies are homogeneous populations of antibodies to a particular antigenic determinant (e.g., a cancer or immune cell antigen, a protein, a peptide, a carbohydrate, a chemical, nucleic acid, or fragments thereof). A monoclonal antibody (mAb) to an antigen-of-interest can be prepared by using any technique known in the art which provides for the production of antibody molecules by continuous cell lines in culture. [0431] Useful monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, or chimeric human-mouse (or other species) monoclonal antibodies. The antibodies include full-length antibodies and antigen binding fragments thereof. Human monoclonal antibodies may be made by any of numerous techniques known in the art (e.g., Teng et al., 1983, Proc. Natl. Acad. Sci. USA. 80:7308- 7312; Kozbor et al., 1983, Immunology Today 4:72-79; and Olsson et al., 1982, Meth. Enzymol. 92:3-16). [0432] In some embodiments, an antibody includes a functionally active fragment, derivative or analog of an antibody that binds specifically to target cells (e.g., cancer cell antigens) or other antibodies bound to cancer cells or matrix. In this regard, “functionally active” means that the fragment, derivative or analog is able to bind specifically to target cells. To determine which CDR sequences bind the antigen, synthetic peptides containing the CDR sequences are typically used in binding assays with the antigen by any binding assay method known in the art (e.g., the Biacore assay) (See, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md; Kabat E et al., 1980, J. Immunology 125(3):961-969). [0433] Additionally, recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which are typically obtained using standard recombinant DNA techniques, are useful antibodies. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as for example, those having a variable region derived from a murine monoclonal and a constant region derived from a human immunoglobulin. See, e.g., U.S. Patent No. 4,816,567; and U.S. Patent No. 4,816,397, which are incorporated herein by reference in their entireties. Humanized antibodies are antibody molecules from non-human species having one or more CDRs from the non-human species and a framework region from a human immunoglobulin molecule. See, e.g., U.S. Patent No. 5,585,089, which is incorporated herein by reference in its entirety. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA techniques known in the art, for example using methods described in International Publication No. WO 87/02671; European Patent Publication No. 0184187; European Patent Publication No. 0171496; European Patent Publication No. 0173494; International Publication No. WO 86/01533; U.S. Patent No. 4,816,567; European Patent Publication No. 012023; Berter et al., 1988, Science 240:1041-1043; Liu et al., 1987, Proc. Natl. Acad. Sci. USA 84:3439-3443; Liu et al., 1987, J. Immunol. 139:3521-3526; Sun et al., 1987, Proc. Natl. Acad. Sci. USA 84:214-218; Nishimura et al., 1987, Cancer. Res. 47:999- 1005; Wood et al., 1985, Nature 314:446-449; and Shaw et al., 1988, J. Natl. Cancer Inst. 80:1553-1559; Morrison, 1985, Science 229:1202-1207; Oi et al., 1986, BioTechniques 4:214; U.S. Patent No. 5,225,539; Jones et al., 1986, Nature 321: 522-525; Verhoeyan et al., 1988, Science 239:1534; and Beidler et al., 1988, J. Immunol. 141:4053-4060; each of which is incorporated herein by reference in its entirety. [0434] In some embodiments, an antibody is a completely human antibody. In some embodiments, an antibody is produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chain genes, but which are capable of expressing human heavy and light chain genes. [0435] In some embodiments, an antibody is an intact or fully-reduced antibody. The term ‘fully-reduced’ is meant to refer to an antibody in which all four inter-chain disulfide linkages have been reduced to provide eight thiols that can be attached to a linker (L). [0436] Attachment to an antibody can be via thioether linkages from native and/or engineered cysteine residues, or from an amino acid residue engineered to participate in a cycloaddition reaction (such as a click reaction) with the corresponding linker intermediate. See, e.g., Maerle, et al., PLOS One 2019: 14(1); e0209860. In some embodiments, an antibody is an intact or fully-reduced antibody, or is an antibody bearing engineered an cysteine group that is modified with a functional group that can participate in, for example, click chemistry or other cycloaddition reactions for attachment of other components of the ADC as described herein (e.g., Diels-Alder reactions or other [3+2] or [4+2] cycloadditions). See, e.g., Agard, et al., J. Am. Chem. Soc. Vol. 126, pp. 15046-15047 (2004); Laughlin, et al., Science, Vol. 320, pp. 664-667 (2008); Beatty, et al., ChemBioChem, Vol. 11, pp. 2092-2095 (2010); and Van Geel, et al., Bioconjug. Chem. Vol. 26, pp.2233-2242 (2015). [0437] Antibodies that bind specifically to a cancer or immune cell antigen are available commercially or produced by any method known to one of skill in the art such as, e.g., chemical synthesis or recombinant expression techniques. The nucleotide sequences encoding antibodies that bind specifically to a cancer or immune cell antigen are obtainable, e.g., from the GenBank database or similar database, literature publications, or by routine cloning and sequencing. [0438] In some embodiments, the antibody can be used for the treatment of a cancer (e.g., an antibody approved by the FDA and/or EMA). Antibodies that bind specifically to a cancer or immune cell antigen are available commercially or produced by any method known to one of skill in the art such as, e.g., recombinant expression techniques. The nucleotide sequences encoding antibodies that bind specifically to a cancer or immune cell antigen are obtainable, e.g., from the GenBank database or similar database, literature publications, or by routine cloning and sequencing. [0439] In some cases, the antibody has a mutation or post-translational modification which affects non-Fab mediated uptake. Peripheral immune cells, which are highly responsive to TLR7/8 agonists can facilitate strong, systemic responses when activated through non-antigen specific, Fc-mediated uptake of the TLR7/8 antibody drug conjugate which may be harmful or otherwise undesirable. In such cases, the antibody can have an effector function-diminishing mutation, such as L234A/L235A, D265A/N297A, D270A, K322A, P329A, P329G or a combination thereof, which diminishes non-immune uptake (e.g., FcgR-mediated uptake). [0440] In some embodiments, an antibody can be configured to bind to a surface antigen of a cell. The antibody, or a complex comprising the antibody, can be configured to internalize within a cell upon binding to the surface antigen. For example, the antibody or an ADC comprising the antibody can be configured to endocytose upon binding to a surface antigen of a cell. In some embodiments, the antibody (or an ADC comprising the antibody) is configured to internalize within a cancer cell. In some embodiments, the antibody (or an ADC comprising the antibody) is configured to internalize within an immune cell. In some embodiments, the immune cell is a tumor associated macrophage. In some embodiments, the surface antigen is a receptor or a receptor complex (e.g., expressed on lymphocytes). In some embodiments, the receptor or receptor complex comprises an immunoglobulin gene superfamily member, a TNF receptor superfamily member, an integrin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement control protein or other immune cell expressed surface receptor. [0441] In some embodiments, an antibody is configured to bind specifically to a cancer cell antigen. In some embodiments, an antibody is configured to bind specifically to an immune cell antigen. In some embodiments, the immune cell antigen is a tumor associated macrophage antigen. In some embodiments, an antibody is configured to bind specifically to EphA2. It will be understood that the antibody component in an ADC is an antibody in residue form such that “Ab” in the ADC structures described herein incorporates the structure of the antibody. [0442] Non-limiting examples of antibodies that can be used for treatment of cancer and antibodies that bind specifically to tumor associated antigens are disclosed in Franke, A. E., Sievers, E. L., and Scheinberg, D. A., “Cell surface receptor-targeted therapy of acute myeloid leukemia: a review” Cancer Biother Radiopharm. 2000,15, 459-76; Murray, J. L., “Monoclonal antibody treatment of solid tumors: a coming of age” Semin Oncol. 2000, 27, 64-70; Breitling, F., and Dubel, S., Recombinant Antibodies, John Wiley, and Sons, New York, 1998, each of which is hereby incorporated by reference in its entirety. [0443] Non-limiting examples of antigens which antibodies of the present disclosure may target include ADAM12 (e.g., Catalog #14139-1-AP); ADAM9 (e.g., IMGC936); AFP (e.g., ThermoFisher Catalog #PA5-25959); AGR2 (e.g., ThermoFisher Catalog #PA5-34517); AKAP-4 (e.g., Catalog #PA5-52230); ALK (e.g., DLX521); ALPP (e.g., Catalog #MA5- 15652); ALPPL2 (e.g., Catalog #PA5-22336); AMHR2 (e.g., ThermoFisher Catalog #PA5- 13902); androgen receptor (e.g., ThermoFisher Catalog #MA5-13426); ANTXR1 (e.g., Catalog #MA1-91702); ANXA1 (e.g., Catalog #71-3400); ARTN (e.g., ThermoFisher Catalog #PA5-47063); ASCT2 (e.g., idactamab); Axl (e.g., BA3011; tilvestamab); B7-DC (e.g., Catalog #PA5-20344); B7-H3 (e.g., enoblituzumab, omburtamab, MGD009, MGC018, DS-7300); B7-H4 (e.g., Catalog #14-5949-82); B7-H6 (e.g., Catalog #12-6526-42); B7-H7; BAFF-R (e.g., Catalog #14-9117-82); BCMA; BCR-ABL; BMPR2; BORIS; C4.4a; CanAg; C5 complement (e.g., BCD-148; CAN106); CA-125; CA19-9 (e.g., AbGn-7; MVT-5873); CA9 (e.g., girentuximab); CALCR (see, e.g., International Publication No. WO 2015077826); CAMPATH-1 (e.g., alemtuzumab; ALLO-647; ANT1034); carcinoembryonic antigen (e.g., arcitumomab; cergutuzumab; amunaleukin; labetuzumab); CCNB1; CD112 (see, e.g., U.S. Publication No. 20100008928); CD115 (e.g., axatilimab; cabiralizumab; emactuzumab); CD123 (e.g., BAY-943; CSL360); CD137 (e.g., ADG106; CTX-471); CD138; CD142; CD166; CD147 (e.g., gavilimomab; metuzumab); CD155 (e.g., U.S. Publication No. 2018/0251548); CD19 (e.g., ALLO-501); CD20 (e.g., divozilimab; ibritumomab tiuxetan); CD24 (see, e.g., U.S. Patent No. 8,614,301); CD244 (e.g., R&D AF1039); CD247 (e.g., AFM15); CD27 (e.g., varlilumab); CD274 (e.g., adebrelimab; atezolizumab; garivulimab); CD3 (e.g., otelixizumab; visilizumab); CD30 (e.g., iratumumab); CD33 (e.g., lintuzumab; BI 836858; AMG 673); CD288; CD352 (e.g., SGN-CD352A); CD37 (e.g., lilotomab; GEN3009); CD38 (e.g., felzartamab; AMG 424); CD3D; CD3E (e.g., foralumab; teplizumab); CD3G; CD45 (e.g., apamistamab); CD47 (e.g., letaplimab; magrolimab); CD48 (e.g., SGN-CD48A); CD5 (e.g., MAT 304; zolimomab aritox); CD56; CD59; CD70 (e.g., cusatuzumab); CD74 (e.g., milatuzumab); CD79A (see, e.g., International Publication No. WO 2020252110); CD79b; CD96; CD97; CD-262 (e.g., tigatuzumab); CDCP1 (e.g., RG7287); CDH17 (see, e.g., International Publication No. WO 2018115231); CDH3 (e.g., PCA062); CDH6 (e.g., HKT288); CEACAM1; CEACAM5; CEACAM6; CLDN1 (e.g., INSERM anti-Claudin-1); CLDN16; CLDN18.1 (e.g., zolbetuximab); CLDN18.2 (e.g., zolbetuximab); CLDN19; CLDN2 (see, e.g., International Publication No. WO 2018123949); CLEC12A (e.g., tepoditamab); CS1; CLPTM1L; CSPG4 (e.g., U.S. Patent No. 10,822,427); CXCR4 (e.g., ulocuplumab); CYP1B1; c-Met; DCLK1 (see, e.g., International Publication No. WO 2018222675); DDR1; de2-7 EGFR (e.g., MAb 806); DLL-3; DPEP1; DPEP3; DPP4; DR4 (e.g., mapatumumab); DSG2 (see, e.g., U.S. Patent No. 10,836,823); EGF; EGFR; endosialin (e.g., ontuxizumab); ENPP1; EPCAM (e.g., adecatumumab); EPHA receptors; EPHA2; ERBB2 (e.g., trastuzumab); ERBB3; ERVMER34_1; ETV6-AML (e.g., Catalog #PA5-81865); FAS; FasL; Fas-related antigen 1; FBP; FGFR1 (e.g., RG7992); FGFR2 (e.g., aprutumab); FGFR3 (e.g., vofatamab); FGFR4 (e.g., MM-161); FLT3 (e.g., 4G8SDIEM); FN; FN1; FOLR1 (e.g., farletuzumab); FRa; FSHR; FucGM1 (e.g., BMS-986012); FZD5; FZD8; G250; GAGE; GCC; GD2 (e.g., dinutuximab); GD3 (e.g., mitumomab); GITR (e.g., ragifilimab); GloboH; GM2 (e.g., BIW- 8962); GM3 (e.g., racotumomab); gp100; GPA33 (e.g., KRN330); GPC3 (e.g., codrituzumab); gpNMB (e.g., glembatumumab); GPR87; GUCY2C (e.g., indusatumab); HAS3; HAVCR2; HLA-E; HLA-F; HLA-G (e.g., TTX-080); HPV E6 E7; hTERT; ICAM1; IDO1; IFNAR1 (e.g., faralimomab); IFNAR2; IL13Ra2; IL1RAP (e.g., nidanilimab); IL-21R (e.g., PF-05230900); IL-5R (e.g., benralizumab); ITGAV (e.g., abituzumab); ITGB6; ITGB8; KISS1R; L1CAM (e.g., JCAR023); LAG-3 (e.g., encelimab); LAMP1; LCK; legumain; LMP2; LY6G6D (e.g., PA5-23303); LY9 (e.g., PA5-95601); LYPD1 (e.g., ThermoFisher Catalog #PA5-26749); MAD-CT-1; MAD-CT-2; MAGEA1 (e.g., Catalog #MA5-11338); MAGEA3 (e.g., ThermoFisher Catalog #60054-1-IG); MAGEA4 (e.g., Catalog #MA5- 26117); MAGEC2 (e.g., ThermoFisher Catalog #PA5-64010); MELTF (e.g., ThermoFisher Catalog #H00004241-M04A); MerTk (e.g., DS5MMER, Catalog #12-5751-82); a metalloproteinase; MFSD13A; MICA (e.g., 1E2C8, Catalog #66384-1-IG); MICB (e.g., Catalog #MA5-29422); Mincle (e.g., OTI2A8, Catalog #TA505101); MLANA (e.g., Catalog #MA5-15237); ML-IAP (e.g., 88C570, ThermoFisher Catalog #40958); MSLN (e.g., 5B2, Catalog #MA5-11918); MUC1 (e.g., MH1 (CT2), ThermoFisher Catalog #MA5-11202); MUC5AC (e.g., 45M1, Catalog #MA5-12178); MYCN (e.g., NCM-II 100, ThermoFisher Catalog #MA1-170); NA17; NCAM1 (e.g., ThermoFisher Catalog #MA5-11563); Nectin-4 (e.g., enfortumab); NOX1 (e.g., Catalog #PA5-103220); NT5E (e.g., 7G2, ThermoFisher Catalog #41-0200); NY-BR-1 (e.g., NY-BR-1 No. 2, Catalog #MA5-12645); NY-ESO-1 (e.g., E978m, Catalog #35-6200); OX40 (e.g., ABM193); OY-TES1; p53; p53mutant; PAP; PAX3 (e.g., GT1210, ThermoFisher Catalog #MA5-31583); PAX5; PDGFR-B (e.g., rinucumab); PDPN (e.g., ThermoFisher Catalog #14-5381-82); PLAVl; PMSA; polysialic acid (see, e.g., Watzlawik et al. J Nat Sci. 2015; 1(8):e141); PR1; PROM1 (e.g., Catalog #14- 1331-82); PSA (e.g., ThermoFisher Catalog #PA1-38514; Daniels-Wells et al. BMC Cancer 2013; 13:195); PSCA (e.g., AGS-1C4D4); PSMA (e.g., BAY 2315497); PTK7 (e.g., cofetuzumab); PVRIG; Ras mutant (e.g., Shin et al. Sci Adv. 2020; 6(3):eaay2174); RET (e.g., WO2020210551); RGS5 (e.g., TF-TA503075); RhoC (e.g., ThermoFisher Catalog PA5-77866); ROR1 (e.g., cirmtuzumab); ROR2 (e.g., BA3021); ROS1 (e.g., WO 2019107671); Sarcoma translocation breakpoints; SART3 (e.g., TF 18025-1-AP); Sialyl- Thomsen-nouveau-antigen (e.g., Eavarone et al. PLoS One. 2018; 13(7): e0201314); Siglecs 1-16 (see, e.g., Angata et al. Trends Pharmacol Sci. 2015; 36(10): 645–660); SIRPa (e.g., Catalog #17-1729-42); SIRPg (e.g., PA5-104381); SIT1 (e.g., PA5-53825); SLAMF7 (e.g., elotuzumab); SLC10A2 (e.g., ThermoFisher Catalog #PA5-18990); SLC12A2 (e.g., ThermoFisher Catalog #13884-1-AP); SLC17A2 (e.g., ThermoFisher Catalog #PA5- 106752); SLC38A1 (e.g., ThermoFisher Catalog #12039-1-AP); SLC39A5 (e.g., ThermoFisher Catalog #MA5-27260); SLC39A6 (e.g., ladiratuzumab); SLC44A4 (e.g., ASG-5ME); SLC6A15 (e.g., ThermoFisher Catalog #PA5-52586); SLC6A6 (e.g., ThermoFisher Catalog #PA5-53431); SLC7A11 (e.g., ThermoFisher Catalog #PA1-16893); SLC7A5; sLe; SLITRK6 (e.g., sirtratumab); Sperm protein 17 (e.g., BS-5754R); SSX2 (e.g., ThermoFisher Catalog #MA5-24971); survivin (e.g., PA1-16836); TACSTD2 (e.g., PA5- 47074); TAG-72 (e.g., MA1-25956); tenascin; TF (e.g., tisotumab); Tie3; TLR2/4/1 (e.g., tomaralimab); TM4SF5 (e.g., 18239-1-AP); TMEM132A (e.g., Catalog #PA5-62524); TMEM40 (e.g., PA5-60636); TMPRSS11D (e.g., PA5-30927); Tn; TNFRSF12 (e.g., BAY- 356); TRAIL (e.g., Catalog #12-9927-42); TRAIL1; TRP-2 (e.g., PA5-52736); ULBP1/2/3/4/5/6 (e.g., PA5-82302); uPAR (e.g., ATN-658); UPK1B (e.g., ThermoFisher Catalog #PA5-56863); UPK2 (e.g., ThermoFisher Catalog #PA5-60318); UPK3B (e.g., ThermoFisher Catalog #PA5-52696); VEGF (e.g., GNR-011); VEGFR2 (e.g., gentuximab); VSIR (e.g., ThermoFisher Catalog #PA5-52493); WT1 (e.g., ThermoFisher Catalog #MA5- 32215); and XAGE1 (e.g., ThermoFisher Catalog #PA5-46413). [0444] Non-limiting examples of target antigens include Axl (e.g., BA3011; tilvestamab); B7-1 (e.g., galiximab); B7-2 (e.g., Catalog #12-0862-82); B7-DC (e.g., Catalog #PA5- 20344); B7-H3 (e.g., enoblituzumab, omburtamab, MGD009, MGC018, DS-7300); B7-H4 (e.g., Catalog #14-5949-82); B7-H6 (e.g., Catalog #12-6526-42); B7-H7; BAFF-R (e.g., Catalog #14-9117-82); BCMA; C5 complement (e.g., BCD-148; CAN106); CCR4 (e.g., AT008; mogamulizumab-kpkc); CCR8 (e.g., JTX-1811); CD112 (see, e.g., U.S. Publication No. 20100008928); CD115 (e.g., axatilimab; cabiralizumab; emactuzumab); CD123 (e.g., BAY-943; CSL360); CD137 (e.g., ADG106; CTX-471); CD155 (e.g., U.S. Publication No. 2018/0251548); CD163 (e.g., TBI 304H); CD19 (e.g., ALLO-501); CD2 (e.g., BTI-322; siplizumab); CD20 (e.g., divozilimab; ibritumomab); CD24 (see, e.g., U.S. Patent No. 8,614,301); CD244 (e.g., R&D AF1039); CD247 (e.g., AFM15); CD25 (e.g., basiliximab); CD27 (e.g., varlilumab); CD274 (e.g., adebrelimab; atezolizumab; garivulimab); CD278 (e.g., feladilimab; vopratelimab); CD28 (e.g., REGN5668); CD3 (e.g., otelixizumab; visilizumab); CD30 (e.g., iratumumab); CD30L (see, e.g., U.S. Patent No. 9,926,373); CD32 (e.g., mAb 2B6); CD33 (e.g., lintuzumab; BI 836858; AMG 673); CD352 (e.g., SGN- CD352A); CD37 (e.g., lilotomab; GEN3009); CD38 (e.g., felzartamab; AMG 424); CD3D; CD3E (e.g., foralumab; teplizumab); CD3G; CD40 (e.g., dacetuzumab; lucatumumab); CD44 (e.g., RG7356); CD45 (e.g., apamistamab); CD47 (e.g., letaplimab; magrolimab); CD48 (e.g., SGN-CD48A); CD5 (e.g., MAT 304; zolimomab aritox); CD51; CD70 (e.g., cusatuzumab); CD74 (e.g., milatuzumab); CD79A (see, e.g., International Publication No. WO 2020252110); CD83 (e.g., CBT004); CD97; CD262 (e.g., tigatuzumab); CLEC12A (e.g., tepoditamab); CTLA4 (e.g., ipilimumab); CXCR4 (e.g., ulocuplumab); DCIR; DCSIGN (see, e.g., International Publication No. WO 2018134389); Dectin1 (see, e.g., U.S. Patent No. 9,045,542); Dectin2 (e.g., ThermoFisher Catalog #MA5-16250); DR4 (e.g., mapatumumab); endosialin (e.g., ontuxizumab); FasL; FLT3 (e.g., 4G8SDIEM); GITR (e.g., ragifilimab); HAVCR2; HER2; HER3; HLA-DR; HLA-E; HLA-F; HLA-G (e.g., TTX-080); ICAM1; IDO1; IFNAR1 (e.g., faralimomab); IFNAR2; IGF-1R; IL1RAP (e.g., nidanilimab); IL-21R (e.g., PF-05230900); IL-5R (e.g., benralizumab); Integrin αvβ6; LAG-3 (e.g., encelimab); LAMP1; LAYN; LCK; LILRB2; LILRB4; MerTk (e.g., DS5MMER, Catalog #12-5751-82); Mesothelin; MICA (e.g., 1E2C8, Catalog #66384-1-IG); MICB (e.g., Catalog #MA5-29422); MICA; Mincle (e.g., OTI2A8, Catalog #TA505101); MRC1 (e.g., ThermoFisher Catalog #12-2061-82); MUC1; Muc16; NcaPi2B; Nectin-4; OX40 (e.g., ABM193); PD-1 (e.g., balstilimab; budigalimab; geptanolimab); PD-L1; Prolactin receptor; PTK7; PVRIG; ROR-1; Sialyl-Thomsen-nouveau-antigen (e.g., Eavarone et al. PLoS One, 2018; 13(7): e0201314); Siglecs 1-16 (see, e.g., Angata et al. Trends Pharmacol Sci. 2015; 36(10): 645–660); ); SIRPa (e.g., Catalog #17-1729-42); SIRPg (e.g., PA5-104381); SIT1 (e.g., PA5-53825); SLAMF7 (e.g., elotuzumab); SLTRK6; STEAP1; TIGIT (e.g., etigilimab); TLR2/4/1 (e.g., tomaralimab); Trem2 (e.g., PY314); TROP2; Tyrol; ULBP1/2/3/4/5/6 (e.g., PA5-82302); uPAR (e.g., ATN-658); VSIR (e.g., ThermoFisher Catalog #PA5-52493); ZIP6 (Anti- Integrin αvβ6). (i) Heavy Chain and Light Chain Variable Regions [0445] In some cases, an antibody target is selected from the group consisting of ADAM9, ASCT2, Axl, B7-H3, B7H4, BCMA, BCMA, C4.4a, CanAg, CD123, CD138, CD142, CD166, CD19, CD20, CD228, CD25, CD30, CD33, CD352, CD38, CD48, CD56, CD59, CD70, CD74, CD79b, CDCP1, CEACAM5, Claudin-18.2, c-Met, gpNMB, CS1, DLL-3, DPEP-3, EGFR, EpCAM, EphA2, FGFR2, FRa, GCC, gpA33, GPC3, Integrin αvβ6 , h2A2, H2G12/STn, HER2, HER3, ZIP6, IGF-1R, IL1Rap, ITGav/CD51, Mesothelin, MICA, MUC-1, Muc16, NaPi2B, Nectin-4, PD-L1, Prolactin receptor, PTK7, ROR-1, SLAMF7, SLTRK6, STEAP1, TIGIT, and TROP2. [0446] In some cases, an antibody of the present disclosure comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, and wherein: the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 44 and the second sequence is SEQ ID NO: 45; the first sequence is SEQ ID NO: 55 and the second sequence is SEQ ID NO: 56; the first sequence is SEQ ID NO: 69 and the second sequence is SEQ ID NO: 70; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121 and the second sequence is SEQ ID NO: 122; the first sequence is SEQ ID NO: 129 and the second sequence is SEQ ID NO: 130; the first sequence is SEQ ID NO: 137 and the second sequence is SEQ ID NO: 138; the first sequence is SEQ ID NO: 153 and the second sequence is SEQ ID NO: 154; the first sequence is SEQ ID NO: 161 and the second sequence is SEQ ID NO: 162; the first sequence is SEQ ID NO: 169 and the second sequence is SEQ ID NO: 170; the first sequence is SEQ ID NO: 177 and the second sequence is SEQ ID NO: 178; the first sequence is SEQ ID NO: 185 and the second sequence is SEQ ID NO: 186; the first sequence is SEQ ID NO: 193 and the second sequence is SEQ ID NO: 194; the first sequence is SEQ ID NO: 201 and the second sequence is SEQ ID NO: 202; the first sequence is SEQ ID NO: 209 and the second sequence is SEQ ID NO: 210; the first sequence is SEQ ID NO: 217 and the second sequence is SEQ ID NO: 218; the first sequence is SEQ ID NO: 225 and the second sequence is SEQ ID NO: 226; the first sequence is SEQ ID NO: 233 and the second sequence is SEQ ID NO: 234; the first sequence is SEQ ID NO: 241 and the second sequence is SEQ ID NO: 242; the first sequence is SEQ ID NO: 249 and the second sequence is SEQ ID NO: 250; the first sequence is SEQ ID NO: 297 and the second sequence is SEQ ID NO: 298; the first sequence is SEQ ID NO: 307 and the second sequence is SEQ ID NO: 308; the first sequence is SEQ ID NO: 315 and the second sequence is SEQ ID NO: 316; the first sequence is SEQ ID NO: 323 and the second sequence is SEQ ID NO: 324; the first sequence is SEQ ID NO: 331 and the second sequence is SEQ ID NO: 332; the first sequence is SEQ ID NO: 339 and the second sequence is SEQ ID NO: 340; the first sequence is SEQ ID NO: 347 and the second sequence is SEQ ID NO: 348; the first sequence is SEQ ID NO: 355 and the second sequence is SEQ ID NO: 356; the first sequence is SEQ ID NO: 363 and the second sequence is SEQ ID NO: 364; the first sequence is SEQ ID NO: 371 and the second sequence is SEQ ID NO: 372; the first sequence is SEQ ID NO: 379 and the second sequence is SEQ ID NO: 380; the first sequence is SEQ ID NO: 387 and the second sequence is SEQ ID NO: 388; the first sequence is SEQ ID NO: 395 and the second sequence is SEQ ID NO: 396; the first sequence is SEQ ID NO: 403 and the second sequence is SEQ ID NO: 404; the first sequence is SEQ ID NO: 411 and the second sequence is SEQ ID NO: 412; the first sequence is SEQ ID NO: 419 and the second sequence is SEQ ID NO: 420; the first sequence is SEQ ID NO: 427 and the second sequence is SEQ ID NO: 428; the first sequence is SEQ ID NO: 435 and the second sequence is SEQ ID NO: 436; the first sequence is SEQ ID NO: 443 and the second sequence is SEQ ID NO: 444; the first sequence is SEQ ID NO: 451 and the second sequence is SEQ ID NO: 452; the first sequence is SEQ ID NO: 459 and the second sequence is SEQ ID NO: 460; the first sequence is SEQ ID NO: 467 and the second sequence is SEQ ID NO: 468; the first sequence is SEQ ID NO: 475 and the second sequence is SEQ ID NO: 476; the first sequence is SEQ ID NO: 483 and the second sequence is SEQ ID NO: 484; the first sequence is SEQ ID NO: 491 and the second sequence is SEQ ID NO: 492; the first sequence is SEQ ID NO: 501 and the second sequence is SEQ ID NO: 502; the first sequence is SEQ ID NO: 509 and the second sequence is SEQ ID NO: 510; the first sequence is SEQ ID NO: 517 and the second sequence is SEQ ID NO: 518; the first sequence is SEQ ID NO: 525 and the second sequence is SEQ ID NO: 526; the first sequence is SEQ ID NO: 533 and the second sequence is SEQ ID NO: 534; the first sequence is SEQ ID NO: 541 and the second sequence is SEQ ID NO: 542; the first sequence is SEQ ID NO: 549 and the second sequence is SEQ ID NO: 550; the first sequence is SEQ ID NO: 557 and the second sequence is SEQ ID NO: 558; the first sequence is SEQ ID NO: 565 and the second sequence is SEQ ID NO: 566; the first sequence is SEQ ID NO: 574 and the second sequence is SEQ ID NO: 574; the first sequence is SEQ ID NO: 581 and the second sequence is SEQ ID NO: 582; the first sequence is SEQ ID NO: 589 and the second sequence is SEQ ID NO: 590; the first sequence is SEQ ID NO: 597 and the second sequence is SEQ ID NO: 598; the first sequence is SEQ ID NO: 605 and the second sequence is SEQ ID NO: 606; the first sequence is SEQ ID NO: 613 and the second sequence is SEQ ID NO: 614; the first sequence is SEQ ID NO: 621 and the second sequence is SEQ ID NO: 622; the first sequence is SEQ ID NO: 629 and the second sequence is SEQ ID NO: 630; the first sequence is SEQ ID NO: 637 and the second sequence is SEQ ID NO: 638; the first sequence is SEQ ID NO: 645 and the second sequence is SEQ ID NO: 646; the first sequence is SEQ ID NO: 653 and the second sequence is SEQ ID NO: 654; the first sequence is SEQ ID NO: 661 and the second sequence is SEQ ID NO: 662; the first sequence is SEQ ID NO: 669 and the second sequence is SEQ ID NO: 670; the first sequence is SEQ ID NO: 677 and the second sequence is SEQ ID NO: 678; the first sequence is SEQ ID NO: 685 and the second sequence is SEQ ID NO: 686; the first sequence is SEQ ID NO: 693 and the second sequence is SEQ ID NO: 694; the first sequence is SEQ ID NO: 701 and the second sequence is SEQ ID NO: 702; the first sequence is SEQ ID NO: 703 and the second sequence is SEQ ID NO: 704; the first sequence is SEQ ID NO: 711 and the second sequence is SEQ ID NO: 712; the first sequence is SEQ ID NO: 713 and the second sequence is SEQ ID NO: 714; the first sequence is SEQ ID NO: 715 and the second sequence is SEQ ID NO: 716; the first sequence is SEQ ID NO: 731 and the second sequence is SEQ ID NO: 732; the first sequence is SEQ ID NO: 739 and the second sequence is SEQ ID NO: 740; the first sequence is SEQ ID NO: 747 and the second sequence is SEQ ID NO: 748; the first sequence is SEQ ID NO: 755 and the second sequence is SEQ ID NO: 756; the first sequence is SEQ ID NO: 765 and the second sequence is SEQ ID NO: 766; the first sequence is SEQ ID NO: 773 and the second sequence is SEQ ID NO: 774; the first sequence is SEQ ID NO: 781 and the second sequence is SEQ ID NO: 782; the first sequence is SEQ ID NO: 789 and the second sequence is SEQ ID NO: 790; the first sequence is SEQ ID NO: 797 and the second sequence is SEQ ID NO: 798; the first sequence is SEQ ID NO: 805 and the second sequence is SEQ ID NO: 806; the first sequence is SEQ ID NO: 813 and the second sequence is SEQ ID NO: 814; the first sequence is SEQ ID NO: 821 and the second sequence is SEQ ID NO: 822; the first sequence is SEQ ID NO: 829 and the second sequence is SEQ ID NO: 830; the first sequence is SEQ ID NO: 837 and the second sequence is SEQ ID NO: 838; the first sequence is SEQ ID NO: 845 and the second sequence is SEQ ID NO: 846; the first sequence is SEQ ID NO: 853 and the second sequence is SEQ ID NO: 854; the first sequence is SEQ ID NO: 861 and the second sequence is SEQ ID NO: 862; the first sequence is SEQ ID NO: 869 and the second sequence is SEQ ID NO: 870; the first sequence is SEQ ID NO: 877 and the second sequence is SEQ ID NO: 878; the first sequence is SEQ ID NO: 885 and the second sequence is SEQ ID NO: 886; the first sequence is SEQ ID NO: 893 and the second sequence is SEQ ID NO: 894; the first sequence is SEQ ID NO: 900 and the second sequence is SEQ ID NO: 901; the first sequence is SEQ ID NO: 909 and the second sequence is SEQ ID NO: 910; the first sequence is SEQ ID NO: 917 and the second sequence is SEQ ID NO: 918; the first sequence is SEQ ID NO: 925 and the second sequence is SEQ ID NO: 926; the first sequence is SEQ ID NO: 933 and the second sequence is SEQ ID NO: 934; the first sequence is SEQ ID NO: 941 and the second sequence is SEQ ID NO: 942; the first sequence is SEQ ID NO: 943 and the second sequence is SEQ ID NO: 944; the first sequence is SEQ ID NO: 951 and the second sequence is SEQ ID NO: 952; the first sequence is SEQ ID NO: 959 and the second sequence is SEQ ID NO: 960; the first sequence is SEQ ID NO: 967 and the second sequence is SEQ ID NO: 968; the first sequence is SEQ ID NO: 975 and the second sequence is SEQ ID NO: 976; the first sequence is SEQ ID NO: 983 and the second sequence is SEQ ID NO: 984; the first sequence is SEQ ID NO: 991 and the second sequence is SEQ ID NO: 992; the first sequence is SEQ ID NO: 993 and the second sequence is SEQ ID NO: 994; the first sequence is SEQ ID NO: 995 and the second sequence is SEQ ID NO: 996; the first sequence is SEQ ID NO: 1003 and the second sequence is SEQ ID NO: 1004; the first sequence is SEQ ID NO: 1011 and the second sequence is SEQ ID NO: 1012; the first sequence is SEQ ID NO: 1019 and the second sequence is SEQ ID NO: 1020; the first sequence is SEQ ID NO: 1027 and the second sequence is SEQ ID NO: 1028; the first sequence is SEQ ID NO: 1035 and 1036; or the first sequence is SEQ ID NO: 1043 and the second sequence is SEQ ID NO: 1044. [0447] In some cases, an antibody of the present disclosure targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, and TIGIT. For example, in some cases, the antibody comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121 and the second sequence is SEQ ID NO: 122; the first sequence is SEQ ID NO: 129 and the second sequence is SEQ ID NO: 130; the first sequence is SEQ ID NO: 137 and the second sequence is SEQ ID NO: 138; the first sequence is SEQ ID NO: 153 and the second sequence is SEQ ID NO: 154; the first sequence is SEQ ID NO: 161 and the second sequence is SEQ ID NO: 162; the first sequence is SEQ ID NO: 169 and the second sequence is SEQ ID NO: 170; the first sequence is SEQ ID NO: 177 and the second sequence is SEQ ID NO: 178; the first sequence is SEQ ID NO: 185 and the second sequence is SEQ ID NO: 186; the first sequence is SEQ ID NO: 193 and the second sequence is SEQ ID NO: 194; the first sequence is SEQ ID NO: 201 and the second sequence is SEQ ID NO: 202; the first sequence is SEQ ID NO: 209 and the second sequence is SEQ ID NO: 210; the first sequence is SEQ ID NO: 217 and the second sequence is SEQ ID NO: 218; the first sequence is SEQ ID NO: 225 and the second sequence is SEQ ID NO: 226; the first sequence is SEQ ID NO: 233 and the second sequence is SEQ ID NO: 234; the first sequence is SEQ ID NO: 241 and the second sequence is SEQ ID NO: 242; the first sequence is SEQ ID NO: 249 and the second sequence is SEQ ID NO: 250; the first sequence is SEQ ID NO: 629 and the second sequence is SEQ ID NO: 630; the first sequence is SEQ ID NO: 637 and the second sequence is SEQ ID NO: 638; the first sequence is SEQ ID NO: 645 and the second sequence is SEQ ID NO: 646; the first sequence is SEQ ID NO: 653 and the second sequence is SEQ ID NO: 654; the first sequence is SEQ ID NO: 661 and the second sequence is SEQ ID NO: 662; the first sequence is SEQ ID NO: 669 and the second sequence is SEQ ID NO: 670; the first sequence is SEQ ID NO: 677 and the second sequence is SEQ ID NO: 678; the first sequence is SEQ ID NO: 685 and the second sequence is SEQ ID NO: 686; the first sequence is SEQ ID NO: 693 and the second sequence is SEQ ID NO: 694; the first sequence is SEQ ID NO: 701 and the second sequence is SEQ ID NO: 702; the first sequence is SEQ ID NO: 703 and the second sequence is SEQ ID NO: 704; the first sequence is SEQ ID NO: 711 and the second sequence is SEQ ID NO: 712; the first sequence is SEQ ID NO: 713 and the second sequence is SEQ ID NO: 714; the first sequence is SEQ ID NO: 715 and the second sequence is SEQ ID NO: 716; or the first sequence is SEQ ID NO: 1027 and the second sequence is SEQ ID NO: 1028. [0448] In some cases, an antibody of the present disclosure comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO: 113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121 and the second sequence is SEQ ID NO: 122; the first sequence is SEQ ID NO: 129 and the second sequence is SEQ ID NO: 130; the first sequence is SEQ ID NO: 137 and the second sequence is SEQ ID NO: 138; the first sequence is SEQ ID NO: 153 and the second sequence is SEQ ID NO: 154; the first sequence is SEQ ID NO: 161 and the second sequence is SEQ ID NO: 162; the first sequence is SEQ ID NO: 169 and the second sequence is SEQ ID NO: 170; the first sequence is SEQ ID NO: 177 and the second sequence is SEQ ID NO: 178; the first sequence is SEQ ID NO: 185 and the second sequence is SEQ ID NO: 186; the first sequence is SEQ ID NO: 193 and the second sequence is SEQ ID NO: 194; the first sequence is SEQ ID NO: 201 and the second sequence is SEQ ID NO: 202; the first sequence is SEQ ID NO: 209 and the second sequence is SEQ ID NO: 210; the first sequence is SEQ ID NO: 217 and the second sequence is SEQ ID NO: 218; the first sequence is SEQ ID NO: 225 and the second sequence is SEQ ID NO: 226; the first sequence is SEQ ID NO: 233 and the second sequence is SEQ ID NO: 234; the first sequence is SEQ ID NO: 241 and the second sequence is SEQ ID NO: 242; the first sequence is SEQ ID NO: 249 and the second sequence is SEQ ID NO: 250; or the first sequence is SEQ ID NO: 1027 and the second sequence is SEQ ID NO: 1028. In some cases, the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20. [0449] In some cases, the heavy chain variable region has at least 85% sequence identity to the first sequence and the light chain variable region has at least 85% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 90% sequence identity to the first sequence and the light chain variable region has at least 90% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 95% sequence identity to the first sequence and the light chain variable region has at least 95% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 98% sequence identity to the first sequence and the light chain variable region has at least 98% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 99% sequence identity to the first sequence and the light chain variable region has at least 99% sequence identity to the second sequence. In some cases, the heavy chain variable region comprises the first sequence and the light chain variable region comprises the second sequence. (ii) Heavy and Light Chains [0450] In some cases, an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 46 and the second sequence is SEQ ID NO: 48; the first sequence is SEQ ID NO: 47 and the second sequence is SEQ ID NO: 48; the first sequence is SEQ ID NO: 57 and the second sequence is SEQ ID NO: 59; the first sequence is SEQ ID NO: 58 and the second sequence is SEQ ID NO: 59; the first sequence is SEQ ID NO: 60 and the second sequence is SEQ ID NO: 62; the first sequence is SEQ ID NO: 61 and the second sequence is SEQ ID NO: 62; the first sequence is SEQ ID NO: 71 and the second sequence is SEQ ID NO: 73; the first sequence is SEQ ID NO: 72 and the second sequence is SEQ ID NO: 73; the first sequence is SEQ ID NO: 74 and the second sequence is SEQ ID NO: 76; the first sequence is SEQ ID NO: 75 and the second sequence is SEQ ID NO: 76; the first sequence is SEQ ID NO: 85 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 86 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 88 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 89 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 251 and the second sequence is SEQ ID NO: 252; the first sequence is SEQ ID NO: 253 and the second sequence is SEQ ID NO: 254; the first sequence is SEQ ID NO: 255 and the second sequence is SEQ ID NO: 256; the first sequence is SEQ ID NO: 257 and the second sequence is SEQ ID NO: 258; the first sequence is SEQ ID NO: 259 and the second sequence is SEQ ID NO: 260; the first sequence is SEQ ID NO: 261 and the second sequence is SEQ ID NO: 262; the first sequence is SEQ ID NO: 263 and the second sequence is SEQ ID NO: 264; the first sequence is SEQ ID NO: 265 and the second sequence is SEQ ID NO: 266; the first sequence is SEQ ID NO: 267 and the second sequence is SEQ ID NO: 268; the first sequence is SEQ ID NO: 269 and the second sequence is SEQ ID NO: 270; the first sequence is SEQ ID NO: 271 and the second sequence is SEQ ID NO: 272; the first sequence is SEQ ID NO: 273 and the second sequence is SEQ ID NO: 274; the first sequence is SEQ ID NO: 275 and the second sequence is SEQ ID NO: 276; the first sequence is SEQ ID NO: 277 and the second sequence is SEQ ID NO: 278; the first sequence is SEQ ID NO: 279 and the second sequence is SEQ ID NO: 280; the first sequence is SEQ ID NO: 281 and the second sequence is SEQ ID NO: 282; the first sequence is SEQ ID NO: 283 and the second sequence is SEQ ID NO: 284; the first sequence is SEQ ID NO: 285 and the second sequence is SEQ ID NO: 286; the first sequence is SEQ ID NO: 287 and the second sequence is SEQ ID NO: 288; the first sequence is SEQ ID NO: 289 and the second sequence is SEQ ID NO: 290; the first sequence is SEQ ID NO: 299 and the second sequence is SEQ ID NO: 300; the first sequence is SEQ ID NO: 493 and the second sequence is SEQ ID NO: 494; the first sequence is SEQ ID NO: 717 and the second sequence is SEQ ID NO: 718; the first sequence is SEQ ID NO: 719 and the second sequence is SEQ ID NO: 720; the first sequence is SEQ ID NO: 721 and the second sequence is SEQ ID NO: 722; the first sequence is SEQ ID NO: 723 and the second sequence is SEQ ID NO: 724; or the first sequence is SEQ ID NO: 757 and the second sequence is SEQ ID NO: 758. [0451] In some cases, an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 85 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 86 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 88 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 89 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 251 and the second sequence is SEQ ID NO: 252; the first sequence is SEQ ID NO: 253 and the second sequence is SEQ ID NO: 254; the first sequence is SEQ ID NO: 255 and the second sequence is SEQ ID NO: 256; the first sequence is SEQ ID NO: 257 and the second sequence is SEQ ID NO: 258; the first sequence is SEQ ID NO: 259 and the second sequence is SEQ ID NO: 260; the first sequence is SEQ ID NO: 261 and the second sequence is SEQ ID NO: 262; the first sequence is SEQ ID NO: 263 and the second sequence is SEQ ID NO: 264; the first sequence is SEQ ID NO: 265 and the second sequence is SEQ ID NO: 266; the first sequence is SEQ ID NO: 267 and the second sequence is SEQ ID NO: 268; the first sequence is SEQ ID NO: 269 and the second sequence is SEQ ID NO: 270; the first sequence is SEQ ID NO: 271 and the second sequence is SEQ ID NO: 272; the first sequence is SEQ ID NO: 273 and the second sequence is SEQ ID NO: 274; the first sequence is SEQ ID NO: 275 and the second sequence is SEQ ID NO: 276; the first sequence is SEQ ID NO: 277 and the second sequence is SEQ ID NO: 278; the first sequence is SEQ ID NO: 279 and the second sequence is SEQ ID NO: 280; the first sequence is SEQ ID NO: 281 and the second sequence is SEQ ID NO: 282; the first sequence is SEQ ID NO: 283 and the second sequence is SEQ ID NO: 284; the first sequence is SEQ ID NO: 285 and the second sequence is SEQ ID NO: 286; the first sequence is SEQ ID NO: 287 and the second sequence is SEQ ID NO: 288; the first sequence is SEQ ID NO: 289 and the second sequence is SEQ ID NO: 290; the first sequence is SEQ ID NO: 717 and the second sequence is SEQ ID NO: 718; the first sequence is SEQ ID NO: 719 and the second sequence is SEQ ID NO: 720; the first sequence is SEQ ID NO: 721 and the second sequence is SEQ ID NO: 722; or the first sequence is SEQ ID NO: 723 and the second sequence is SEQ ID NO: 724. [0452] In some cases, an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 85 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 86 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 88 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 89 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 251 and the second sequence is SEQ ID NO: 252; the first sequence is SEQ ID NO: 253 and the second sequence is SEQ ID NO: 254; the first sequence is SEQ ID NO: 255 and the second sequence is SEQ ID NO: 256; the first sequence is SEQ ID NO: 257 and the second sequence is SEQ ID NO: 258; the first sequence is SEQ ID NO: 259 and the second sequence is SEQ ID NO: 260; the first sequence is SEQ ID NO: 261 and the second sequence is SEQ ID NO: 262; the first sequence is SEQ ID NO: 263 and the second sequence is SEQ ID NO: 264; the first sequence is SEQ ID NO: 265 and the second sequence is SEQ ID NO: 266; the first sequence is SEQ ID NO: 267 and the second sequence is SEQ ID NO: 268; the first sequence is SEQ ID NO: 269 and the second sequence is SEQ ID NO: 270; the first sequence is SEQ ID NO: 271 and the second sequence is SEQ ID NO: 272; the first sequence is SEQ ID NO: 273 and the second sequence is SEQ ID NO: 274; the first sequence is SEQ ID NO: 275 and the second sequence is SEQ ID NO: 276; the first sequence is SEQ ID NO: 277 and the second sequence is SEQ ID NO: 278; the first sequence is SEQ ID NO: 279 and the second sequence is SEQ ID NO: 280; the first sequence is SEQ ID NO: 281 and the second sequence is SEQ ID NO: 282; the first sequence is SEQ ID NO: 283 and the second sequence is SEQ ID NO: 284; the first sequence is SEQ ID NO: 285 and the second sequence is SEQ ID NO: 286; the first sequence is SEQ ID NO: 287 and the second sequence is SEQ ID NO: 288; or the first sequence is SEQ ID NO: 289 and the second sequence is SEQ ID NO: 290. [0453] In some cases, an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; or the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10. [0454] In some cases, an antibody of the present disclosure comprises a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 3 or SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5. [0455] In some cases, the heavy chain has at least 85% sequence identity to the first sequence and the light chain has at least 85% sequence identity to the second sequence. In some cases, the heavy chain has at least 90% sequence identity to the first sequence and the light chain has at least 90% sequence identity to the second sequence. In some cases, the heavy chain has at least 95% sequence identity to the first sequence and the light chain has at least 95% sequence identity to the second sequence. In some cases, the heavy chain has at least 98% sequence identity to the first sequence and the light chain has at least 98% sequence identity to the second sequence. In some cases, the heavy chain has at least 99% sequence identity to the first sequence and the light chain has at least 99% sequence identity to the second sequence. In some cases, the heavy chain comprises the first sequence and the light chain comprises the second sequence. (iii) Complementarity-Determining Regions [0456] In some cases, an antibody of the present disclosure comprises CDR-H1, CDR- H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising at least 80% sequence identity to: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively (i.e., CDR-H1 has at least 80% sequence identity to SEQ ID NO: 13, CDR-H2 has at least 80% sequence identity to SEQ ID NO: 14, CDR-H3 has at least 80% sequence identity to SEQ ID NO: 15, CDR-L1 has at least 80% sequence identity to SEQ ID NO: 16, CDR-L2 has at least 80% sequence identity to SEQ ID NO: 17, and CDR-L3 has at least 80% sequence identity to SEQ ID NO: 18); SEQ ID NO: 21, 22, 23, 24, 25, and 26, respectively; SEQ ID NO: 38, 39, 40, 41, 42, and 43, respectively; SEQ ID NO: 49, 50, 51, 52, 53, and 54, respectively; SEQ ID NO: 63, 64, 65, 66, 67, and 68, respectively; SEQ ID NO: 77, 78, 79, 80, 81, and 82, , respectively; SEQ ID NO: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NO: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NO: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NO: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NO: 123, 124, 125, 126, 127, and 128, respectively; SEQ ID NO: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NO: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NO: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NO: 155, 156, 157, 158, 159, and 160, respectively; SEQ ID NO: 163, 164, 165, 166, 167, and 168, respectively; SEQ ID NO: 171, 172, 173, 174, 175, and 176, respectively; SEQ ID NO: 179, 180, 181, 182, 183, and 184, respectively; SEQ ID NO: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NO: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NO: 203, 204, 205, 206, 207 and 208, respectively; SEQ ID NO: 211, 212, 213, 214, 215, and 216, respectively; SEQ ID NO: 219, 220, 221, 222, 223, and 224, respectively; SEQ ID NO: 227, 228, 229, 230, 231, and 232, respectively; SEQ ID NO: 235, 236, 237, 238, 239, and 240, respectively; SEQ ID NO: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NO: 291, 292, 293, 294, 295, and 296, respectively; SEQ ID NO: 301, 302, 303, 304, 305, and 306, respectively; SEQ ID NO: 309, 310, 311, 312, 313, and 314, respectively; SEQ ID NO: 317, 318, 319, 320, 321, and 322, respectively; SEQ ID NO: 325, 326, 327, 328, 329, and 330, respectively; SEQ ID NO: 333, 334, 335, 336, 337, and 338, respectively; SEQ ID NO: 341, 342, 343, 344, 345, and 346, respectively; SEQ ID NO: 349, 350, 351, 352, 353, and 354, respectively; SEQ ID NO: 357, 358, 359, 360, 361, and 362, respectively; SEQ ID NO: 365, 366, 367, 368, 369, and 370, respectively; SEQ ID NO: 373, 374, 375, 376, 377, and 378, respectively; SEQ ID NO: 381, 382, 383, 384, 385, and 386, respectively; SEQ ID NO: 389, 390, 391, 392, 393, and 394, respectively; SEQ ID NO: 397, 398, 399, 400, 401, and 402, respectively; SEQ ID NO: 405, 406, 407, 408, 409, and 410, respectively; SEQ ID NO: 413, 414, 415, 416, 417, and 418, respectively; SEQ ID NO: 421, 422, 423, 424, 425, and 426, respectively; SEQ ID NO: 429, 430, 431, 432, 433, and 434, respectively; SEQ ID NO: 437, 438, 439, 440, 441, and 442, respectively; SEQ ID NO: 445, 446, 447, 448, 449, and 450, respectively; SEQ ID NO: 453, 454, 455, 456, 457, and 458, respectively; SEQ ID NO: 461, 462, 463, 464, 465, and 466, respectively; SEQ ID NO: 469, 470, 471, 472, 473, and 474, respectively; SEQ ID NO: 477, 478, 479, 480, 481, and 482, respectively; SEQ ID NO: 485, 486, 487, 488, 489, and 490, respectively; SEQ ID NO: 495, 496, 497, 498, 499, and 500, respectively; SEQ ID NO: 503, 504, 505, 506, 507, and 508, respectively; SEQ ID NO: 511, 512, 513, 514, 515, and 516, respectively; SEQ ID NO: 519, 520, 521, 522, 523, and 524, respectively; SEQ ID NO: 527, 528, 529, 530, 531, and 532, respectively; SEQ ID NO: 535, 536, 537, 538, 539, and 540, respectively; SEQ ID NO: 543, 544, 545, 546, 547, and 548, respectively; SEQ ID NO: 551, 552, 553, 554, 555, and 556, respectively; SEQ ID NO: 559, 560, 561, 562, 563, and 564, respectively; SEQ ID NO: 567, 568, 569, 570, 571, and 572, respectively; SEQ ID NO: 575, 576, 577, 578, 579, and 580, respectively; SEQ ID NO: 583, 584, 585, 586, 587, and 588, respectively; SEQ ID NO: 591, 592, 593, 594, 595, and 596, respectively; SEQ ID NO: 599, 600, 601, 602, 603, and 604, respectively; SEQ ID NO: 607, 608, 609, 610, 611, and 612, respectively; SEQ ID NO: 615, 616, 617, 618, 619, and 620, respectively; SEQ ID NO: 623, 624, 625, 626, 627, and 628, respectively; SEQ ID NO: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NO: 639, 640, 641, 642, 643, and 644, respectively; SEQ ID NO: 647, 648, 649, 650, 651, and 652, respectively; SEQ ID NO: 655, 656, 657, 658, 659, and 660, respectively; SEQ ID NO: 663, 664, 665, 666, 667, and 668, respectively; SEQ ID NO: 671, 672, 673, 674, 675, and 676, respectively; SEQ ID NO: 679, 680, 681, 682, 683, and 684, respectively; SEQ ID NO: 687, 688, 689, 690, 691, and 692, respectively; SEQ ID NO: 695, 696, 697, 698, 699, and 700, respectively; SEQ ID NO: 705, 706, 707, 708, 709, and 710, respectively; SEQ ID NO: 725, 726, 727, 728, 729, and 730, respectively; SEQ ID NO: 733, 734, 735, 736, 737, and 738, respectively; SEQ ID NO: 741, 742, 743, 744, 745, and 746, respectively; SEQ ID NO: 749, 750, 751, 752, 753, and 754, respectively; SEQ ID NO: 759, 760, 761, 762, 763, and 764, respectively; SEQ ID NO: 767, 768, 769, 770, 771, and 772, respectively; SEQ ID NO: 775, 776, 777, 778, 779, and 780, respectively; SEQ ID NO: 783, 784, 785, 786, 787, and 788, respectively; SEQ ID NO: 791, 792, 793, 794, 795, and 796, respectively; SEQ ID NO: 799, 800, 801, 802, 803, and 804, respectively; SEQ ID NO: 807, 808, 809, 810, 811, and 812, respectively; SEQ ID NO: 815, 816, 817, 818, 819, and 820, respectively; SEQ ID NO: 823, 824, 825, 826, 827, and 828, respectively; SEQ ID NO: 831, 832, 833, 834, 835, and 836, respectively; SEQ ID NO: 839, 840, 841, 842, 843, and 844, respectively; SEQ ID NO: 847, 848, 849, 850, 851, and 852, respectively; SEQ ID NO: 855, 856, 857, 858, 859, and 860, respectively; SEQ ID NO: 863, 864, 865, 866, 867, and 868, respectively; SEQ ID NO: 871, 872, 873, 874, 875, and 876, respectively; SEQ ID NO: 879, 880, 881, 882, 883, and 884, respectively; SEQ ID NO: 887, 888, 889, 890, 891, and 892, respectively; SEQ ID NO: 895, 896, 897, 898, 899, and 900, respectively; SEQ ID NO: 903, 904, 905, 906, 907, and 908, respectively; SEQ ID NO: 911, 912, 913, 914, 915, and 916, respectively; SEQ ID NO: 919, 920, 921, 922, 923, and 924, respectively; SEQ ID NO: 927, 928, 929, 930, 931, and 932, respectively; SEQ ID NO: 935, 936, 937, 938, 939, and 940, respectively; SEQ ID NO: 945, 946, 947, 948, 949, and 950, respectively; SEQ ID NO: 953, 954, 955, 956, 957, and 958, respectively; SEQ ID NO: 961, 962, 963, 964, 965, and 966, respectively; SEQ ID NO: 969, 970, 971, 972, 973, and 974, respectively; SEQ ID NO: 977, 978, 979, 980, 981, and 982, respectively; SEQ ID NO: 985, 986, 987, 988, 989, and 990, respectively; SEQ ID NO: 997, 998, 999, 1000, 1001, and 1002, respectively; SEQ ID NO: 1005, 1006, 1007, 1008, 1009, and 1010, respectively; SEQ ID NO: 1013, 1014, 1015, 1016, 1017, and 1018, respectively; SEQ ID NO: 1021, 1022, 1023, 1024, 1025, and 1026, respectively; SEQ ID NO: 1029, 1030, 1031, 1032, 1033, and 1034, respectively; or SEQ ID NO: 1037, 1038, 1039, 1040, 1041, and 1042, respectively. [0457] In some cases, an antibody of the present disclosure targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, and TIGIT. For example, in some cases, an antibody of the present disclosure comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 comprising at least 80% sequence identity to: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NO: 77, 78, 79, 80, 81, and 82, , respectively; SEQ ID NO: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NO: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NO: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NO: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NO: 123, 124, 125, 126, 127, and 128, respectively; SEQ ID NO: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NO: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NO: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NO: 155, 156, 157, 158, 159, and 160, respectively; SEQ ID NO: 163, 164, 165, 166, 167, and 168, respectively; SEQ ID NO: 171, 172, 173, 174, 175, and 176, respectively; SEQ ID NO: 179, 180, 181, 182, 183, and 184, respectively; SEQ ID NO: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NO: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NO: 203, 204, 205, 206, 207 and 208, respectively; SEQ ID NO: 211, 212, 213, 214, 215, and 216, respectively; SEQ ID NO: 219, 220, 221, 222, 223, and 224, respectively; SEQ ID NO: 227, 228, 229, 230, 231, and 232, respectively; SEQ ID NO: 235, 236, 237, 238, 239, and 240, respectively; SEQ ID NO: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NO: 623, 624, 625, 626, 627, and 628, respectively; SEQ ID NO: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NO: 639, 640, 641, 642, 643, and 644, respectively; SEQ ID NO: 647, 648, 649, 650, 651, and 652, respectively; SEQ ID NO: 655, 656, 657, 658, 659, and 660, respectively; SEQ ID NO: 663, 664, 665, 666, 667, and 668, respectively; SEQ ID NO: 671, 672, 673, 674, 675, and 676, respectively; SEQ ID NO: 679, 680, 681, 682, 683, and 684, respectively; SEQ ID NO: 687, 688, 689, 690, 691, and 692, respectively; SEQ ID NO: 695, 696, 697, 698, 699, and 700, respectively; SEQ ID NO: 705, 706, 707, 708, 709, and 710, respectively; or SEQ ID NO: 1021, 1022, 1023, 1024, 1025, and 1026, respectively. [0458] In some cases, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise at least 85% sequence identity to the respective 6 indicated sequences. In some cases, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprise at least 90% sequence identity to the respective 6 indicated sequences. In some cases, the CDR- H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprise at least 95% sequence identity to the respective 6 indicated sequences. In some cases, the CDR-H1, CDR- H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprise at most one mutation relative to the respective 6 indicated sequences. (iv) Exemplary Antibodies [0459] In some cases, an antibody provided herein binds to PDL1. PDL1 is expressed in a broad range of cancers, as well as certain immune cells, and often serves as a primary mechanism for immune suppression in tumor microenvironments. The PDL1 agonism of PD- 1 can act as an immune checkpoint, diminishing lymphocyte tumor infiltration, and T-cell receptor mediated proliferation and signaling. While PDL1 antagonism can reverse immune suppression, PDL1 targeting can also localize treatments to the sites of cancers, allowing drugs to selectively target cancer cells or stimulate immune responses in the presence of tumors. [0460] In some cases, an anti-PDL1 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18 respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively. [0461] In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 1-4 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 3 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 4 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. [0462] In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 6- 9 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 6 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 8 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 9 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10. [0463] In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 20. [0464] In some embodiments, an antibody provided herein binds to EphA2. In some embodiments, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequences of SEQ ID NOs: 21, 22, 23, 24, 25, and 26, respectively. [0465] In some embodiments, the anti-EphA2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, the anti-EphA2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of the amino acid sequence of SEQ ID NO: 31. In some embodiments, the anti-EphA2 antibody comprises a heavy chain comprising the amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 34. In some embodiments, the anti-EphA2 antibody comprises a heavy chain that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 35 or SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the antibody is h1C1 or 1C1. [0466] In some embodiments, the anti-EphA2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 28. [0467] In some cases, an antibody provided herein binds to CD30. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively. In some embodiments, the anti-CD30 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 46 or 47 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 44 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 45. [0468] In some cases, an antibody provided herein binds to CD228. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively. In some embodiments, the anti-CD228 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the anti-CD228 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either of SEQ ID NO: 57 or 58 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-CD228 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either of SEQ ID NO: 60 or 61 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 62. [0469] In some cases, an antibody provided herein binds to avB6. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively. In some embodiments, the anti-H2A2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70. In some embodiments, the anti-H2A2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 71 or 72 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the anti-H2A2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 74 or 75 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76. In some embodiments, the anti-avB6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70. In some embodiments, the anti-avB6 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 71 or 72 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the anti-avB6 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 74 or 75 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76. [0470] In some cases, an antibody provided herein binds to B7H4. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 77-82, SEQ ID NOs: 91-96, SEQ ID NOs: 99-104, SEQ ID NOs: 107-112, SEQ ID NOs: 115-120, SEQ ID NOs: 123-128, SEQ ID NOs: 131- 136, SEQ ID NOs: 139-144, SEQ ID NOs: 147-152, SEQ ID NOs: 155-160, SEQ ID NOs: 163-168, SEQ ID NOs: 171-176, SEQ ID NOs: 179-184, SEQ ID NOs: 187-192, SEQ ID NOs: 195-200, SEQ ID NOs: 203-208, SEQ ID NOs: 211-216, SEQ ID NOs: 219-224, SEQ ID NOs: 227-232, SEQ ID NOs: 235-240, and SEQ ID NOs: 243-248. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3, respectively) each comprising at most one mutation relative to an amino acid sequence from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 77-82, SEQ ID NOs: 91-96, SEQ ID NOs: 99-104, SEQ ID NOs: 107-112, SEQ ID NOs: 115-120, SEQ ID NOs: 123-128, SEQ ID NOs: 131-136, SEQ ID NOs: 139-144, SEQ ID NOs: 147-152, SEQ ID NOs: 155-160, SEQ ID NOs: 163-168, SEQ ID NOs: 171-176, SEQ ID NOs: 179-184, SEQ ID NOs: 187-192, SEQ ID NOs: 195-200, SEQ ID NOs: 203- 208, SEQ ID NOs: 211-216, SEQ ID NOs: 219-224, SEQ ID NOs: 227-232, SEQ ID NOs: 235-240, and SEQ ID NOs: 243-248. In some cases, the anti-B7H4 antibody comprises a heavy chain and a light chain comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 85 and 87, SEQ ID NO: 86 and 87, SEQ ID NO: 88 and 90, SEQ ID NO: 89 and 90, SEQ ID NO: 251 and 252, , SEQ ID NO: 253 and 254, SEQ ID NO: 255 and 256, SEQ ID NO: 257 and 258, SEQ ID NO: 259 and 260, SEQ ID NO: 261 and 262, SEQ ID NO: 263 and 264, SEQ ID NO: 265 and 266, SEQ ID NO: 267 and 268, SEQ ID NO: 269 and 270, SEQ ID NO: 271 and 272, SEQ ID NO: 273 and 274, SEQ ID NO: 275 and 276, SEQ ID NO: 277 and 278, SEQ ID NO: 279 and 280, SEQ ID NO: 281 and 282, SEQ ID NO: 283 and 284, SEQ ID NO: 285 and 286, SEQ ID NO: 287 and 288, or SEQ ID NO: 289 and 290, respectively. In some embodiments, the anti-B7H4 antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 83 and 84, SEQ ID NO: 97 and 98, SEQ ID NO: 105 and 106, SEQ ID NO: 113 and 114, SEQ ID NO: 121 and 122, SEQ ID NO: 129 and 130, SEQ ID NO: 137 and 138, SEQ ID NO: 153 and 154, SEQ ID NO: 161 and 162, SEQ ID NO: 169 and 170, SEQ ID NO: 177 and 178, SEQ ID NO: 185 and 186, SEQ ID NO: 193 and 194, SEQ ID NO: 201 and 202, SEQ ID NO: 209 and 210, SEQ ID NO: 217 and 218, SEQ ID NO: 225 and 226, SEQ ID NO: 233 and 234, SEQ ID NO: 241 and 242, or SEQ ID NO: 249 and 250, respectively. [0471] In some cases, an antibody provided herein binds to CD70. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively. In some embodiments, the anti-CD70 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 297 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 298. In some embodiments, the anti- CD70 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 299 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 300. [0472] In some cases, an antibody provided herein binds to TROP2. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively. In some cases, an antibody provided herein binds to TROP2. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 309, 310, 311, 312, 313, and 314 respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 309, 310, 311, 312, 313, and 314, respectively. In some embodiments, the anti-TROP2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 307 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 308. In some embodiments, the anti-TROP2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 315 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 316. [0473] In some cases, an antibody provided herein binds to MICA. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively. In some embodiments, the anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 323 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 324. In some embodiments, the anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 331 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 332. In some embodiments, the anti- MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 340 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 340. In some embodiments, the anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 347 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 348. [0474] In some cases, an antibody provided herein binds to CD51. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively. In some cases, an antibody provided herein binds to CD51. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 357, 358, 359, 360, 361, and 362, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 357, 358, 359, 360, 361, and 362, respectively. In some embodiments, the anti-CD51 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 355 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 356. In some embodiments, the anti-CD51 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 363 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 364. [0475] In some cases, an antibody provided herein binds to gpA33. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 365, 366, 367, 368, 369, and 370, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 365, 366, 367, 368, 369, and 370, respectively. In some embodiments, the anti-gpA33 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 371 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 372. [0476] In some cases, an antibody provided herein binds to IL1Rap. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively. In some embodiments, the anti-IL1Rap antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 379 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 380. [0477] In some cases, an antibody provided herein binds to EpCAM. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 381-386, SEQ ID NOs: 389-394, SEQ ID NOs: 397- 402, SEQ ID NOs: 405-410, SEQ ID NOs: 413-418, or SEQ ID NOs: 421-426. In some embodiments, the anti-EpCAM antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 387 and 388, SEQ ID NO: 395 and 396, SEQ ID NO: 403 and 404, SEQ ID NO: 411 and 412, SEQ ID NO: 419 and 420, or SEQ ID NO: 427 and 428, respectively. [0478] In some cases, an antibody provided herein binds to CD352. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively. In some embodiments, the anti-CD352 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 435 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 436. [0479] In some cases, an antibody provided herein binds to CS1. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively. In some embodiments, the anti-CS1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 443 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 444. [0480] In some cases, an antibody provided herein binds to CD38. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 445, 446, 447, 448, 449, and 450, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 445, 446, 447, 448, 449, and 450, respectively. In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 451 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 452. [0481] In some cases, an antibody provided herein binds to CD25. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively. In some embodiments, the anti-CD25 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 459 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 460. [0482] In some cases, an antibody provided herein binds to ADAM9. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively. In some such cases, the antibody comprises CDR- H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 469, 470, 471, 472, 473, and 474, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 469, 470, 471, 472, 473, and 474, respectively. In some embodiments, the anti-ADAM9 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 467 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 468. In some embodiments, the anti-ADAM9 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 475 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 476. [0483] In some cases, an antibody provided herein binds to CD59. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 477, 478, 479, 480, 481, and 482, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 477, 478, 479, 480, 481, and 482, respectively. In some embodiments, the anti-CD59 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 483 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 484. [0484] In some cases, an antibody provided herein binds to CD19. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 485, 486, 487, 488, 489, and 490, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 485, 486, 487, 488, 489, and 490, respectively. In some embodiments, the anti-CD19 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 491 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 492. In some embodiments, the anti- CD19 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 493 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 494. [0485] In some cases, an antibody provided herein binds to CD138. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 495, 496, 497, 498, 499, and 500, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 495, 496, 497, 498, 499, and 500, respectively. In some embodiments, the anti-CD138 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 501 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 502. [0486] In some cases, an antibody provided herein binds to CD166. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 503, 504, 505, 506, 507, and 508, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 503, 504, 505, 506, 507, and 508, respectively. In some embodiments, the anti-CD166 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 509 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 510. [0487] In some cases, an antibody provided herein binds to CD56. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively. In some embodiments, the anti-CD56 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 517 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 518. [0488] In some cases, an antibody provided herein binds to CD74. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 519, 520, 521, 522, 523, and 524, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 519, 520, 521, 522, 523, and 524, respectively. In some embodiments, the anti-CD74 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 525 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 526. [0489] In some cases, an antibody provided herein binds to CEACAM5. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 527, 528, 529, 530, 531, and 532, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 527, 528, 529, 530, 531, and 532, respectively. In some embodiments, the anti-CEACAM5 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 533 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 534. [0490] In some cases, an antibody provided herein binds to CanAg. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively. In some embodiments, the anti-CanAg antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 541 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 542. [0491] In some cases, an antibody provided herein binds to DLL-3. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 543, 544, 545, 546, 547, and 548, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 543, 544, 545, 546, 547, and 548, respectively. In some embodiments, the anti-DLL-3 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 549 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 550. [0492] In some cases, an antibody provided herein binds to DPEP-3. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 551, 552, 553, 554, 555, and 556, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 551, 552, 553, 554, 555, and 556, respectively. In some embodiments, the anti-DPEP-3 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 557 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 558. [0493] In some cases, an antibody provided herein binds to EGFR. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 559-564, SEQ ID NOs: 567-572, SEQ ID NOs: 575- 580, and SEQ ID NOs: 895-900. In some embodiments, the anti-EGFR antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 565 and 566, SEQ ID NO: 573 and 574, SEQ ID NO: 581 and 582, or SEQ ID NO: 901 and 902, respectively. [0494] In some cases, an antibody provided herein binds to FRa. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 583, 584, 585, 586, 587, and 588, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 583, 584, 585, 586, 587, and 588, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 591, 592, 593, 594, 595, and 596, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 591, 592, 593, 594, 595, and 596, respectively. In some embodiments, the anti-FRa antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 589 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 590. In some embodiments, the anti-FRa antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 597 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 598. [0495] In some cases, an antibody provided herein binds to MUC-1. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 599, 600, 601, 602, 603, and 604, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 599, 600, 601, 602, 603, and 604, respectively. In some embodiments, the anti-MUC-1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 605 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 606. [0496] In some cases, an antibody provided herein binds to Mesothelin. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 607, 608, 609, 610, 611, and 612, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 607, 608, 609, 610, 611, and 612, respectively. In some embodiments, the anti-Mesothelin antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 613 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 614. [0497] In some cases, an antibody provided herein binds to ROR-1. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 615, 616, 617, 618, 619, and 620, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 615, 616, 617, 618, 619, and 620, respectively. In some embodiments, the anti-ROR-1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 621 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 622. [0498] In some cases, an antibody provided herein binds to B7H3. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR- L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 623-628, SEQ ID NOs: 631-636, SEQ ID NOs: 639- 644, SEQ ID NOs: 647-652, SEQ ID NOs: 655-660, SEQ ID NOs: 663-668, SEQ ID NOs: 671-676, SEQ ID NOs: 679-684, SEQ ID NOs: 687-692, SEQ ID NOs: 695-700, and SEQ ID NOs: 705-710. In some embodiments, the anti-B7H3 antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 629 and 630, SEQ ID NOs: 637 and 638, SEQ ID NOs: 645 and 646, SEQ ID NOs: 653 and 654, SEQ ID NOs: 661 and 662, SEQ ID NOs: 669 and 670, SEQ ID NOs: 677 and 678, SEQ ID NOs: 685 and 686, SEQ ID NOs: 693 and 694, SEQ ID NOs: 701 and 702, SEQ ID NOs: 703 and 704, SEQ ID NOs: 711 and 712, SEQ ID NOs: 713 and 714, and SEQ ID NOs: 715 and 716, respectively. [0499] In some cases, an antibody provided herein binds to HER3. In some embodiments, the anti-HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 717 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 718. In some cases, an antibody provided herein binds to HER3. In some embodiments, the anti-HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 719 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 720. In some cases, an antibody provided herein binds to HER3. In some embodiments, the anti-HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 721 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 722. In some cases, an antibody provided herein binds to HER3. In some embodiments, the anti-HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 723 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 724. [0500] In some cases, an antibody provided herein binds to PTK7. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 725, 726, 727, 728, 729, and 730, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 725, 726, 727, 728, 729, and 730, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 733, 734, 735, 736, 737, and 738, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 733, 734, 735, 736, 737, and 738, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 741, 742, 743, 744, 745, and 746, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 741, 742, 743, 744, 745, and 746, respectively. In some cases, the anti-PTK7 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 731 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 732. In some cases, the anti-PTK7 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 739 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 740. In some cases, the anti-PTK7 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 747 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 748. [0501] In some cases, an antibody provided herein binds to ZIP6. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 749, 750, 751, 752, 753, and 754, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 749, 750, 751, 752, 753, and 754, respectively. In some cases, the anti-ZIP6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 755 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 756. In some embodiments, the anti-ZIP6 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 757 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 758. [0502] In some cases, an antibody provided herein binds to Integrin αvβ6. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 759, 760, 761, 762, 763, and 764, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 759, 760, 761, 762, 763, and 764, respectively. In some embodiments, the anti- Integrin αvβ6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 765 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 766. [0503] In some cases, an antibody provided herein binds to CD48. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 767, 768, 769, 770, 771, and 772, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 767, 768, 769, 770, 771, and 772, respectively. In some embodiments, the anti-CD48 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 773 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 774. [0504] In some cases, an antibody provided herein binds to IGF-1R. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 775, 776, 777, 778, 779, and 780, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 775, 776, 777, 778, 779, and 780, respectively. In some embodiments, the anti-IGF-1R antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 781 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 782. [0505] In some cases, an antibody provided herein binds to Claudin-18.2. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 783, 784, 785, 786, 787, and 788, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 783, 784, 785, 786, 787, and 788, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 791, 792, 793, 794, 795, and 796, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 791, 792, 793, 794, 795, and 796, respectively. In some embodiments, the anti-Claudin-18.2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 789 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 790. In some embodiments, the anti-Claudin-18.2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 797 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 798. [0506] In some cases, an antibody provided herein binds to Nectin-4. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 799, 800, 801, 802, 803, and 804, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 799, 800, 801, 802, 803, and 804, respectively. In some embodiments, the anti-Nectin-4 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 805 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 806. [0507] In some cases, an antibody provided herein binds to SLTRK6. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 807, 808, 809, 810, 811, and 812, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 807, 808, 809, 810, 811, and 812, respectively. In some embodiments, the anti-SLTRK6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 813 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 814. [0508] In some cases, an antibody provided herein binds to CD142. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 815, 816, 817, 818, 819, and 820, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 815, 816, 817, 818, 819, and 820, respectively. In some embodiments, the anti-CD142 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 821 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 822. [0509] In some cases, an antibody provided herein binds to Sialyl-Thomsen-nouveau antigen (STn). In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 823, 824, 825, 826, 827, and 828, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 823, 824, 825, 826, 827, and 828, respectively. [0510] In some embodiments, the anti-STn antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 829 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 830. [0511] In some cases, an antibody provided herein binds to CD20. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 831, 832, 833, 834, 835, and 836, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 831, 832, 833, 834, 835, and 836, respectively. In some embodiments, the anti-CD20 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 837 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 838. [0512] In some cases, an antibody provided herein binds to HER2. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 839, 840, 841, 842, 843, and 844, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 839, 840, 841, 842, 843, and 844, respectively. In some embodiments, the anti-HER2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 845 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 846. [0513] In some cases, an antibody provided herein binds to CD79b. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 847, 848, 849, 850, 851, and 852, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 847, 848, 849, 850, 851, and 852, respectively. In some embodiments, the anti-CD79b antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 853 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 854. [0514] In some cases, an antibody provided herein binds to NaPi2B. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 855, 856, 857, 858, 859, and 860, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 855, 856, 857, 858, 859, and 860, respectively. In some embodiments, the anti-NaPi2B antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 861 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 862. [0515] In some cases, an antibody provided herein binds to Muc16. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 863, 864, 865, 866, 867, and 868, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 863, 864, 865, 866, 867, and 868, respectively. In some embodiments, the anti-Muc16 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 869 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 870. [0516] In some cases, an antibody provided herein binds to STEAP1. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 871, 872, 873, 874, 875, and 876, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 871, 872, 873, 874, 875, and 876, respectively. In some embodiments, the anti-STEAP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 877 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 878. [0517] In some cases, an antibody provided herein binds to BCMA. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 879, 880, 881, 882, 883, and 884, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 879, 880, 881, 882, 883, and 884, respectively. In some embodiments, the anti-BCMA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 885 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 886. [0518] In some cases, an antibody provided herein binds to c-Met. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 887, 888, 889, 890, 891, and 892, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 887, 888, 889, 890, 891, and 892, respectively. In some embodiments, the anti-c-Met antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 893 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 893. [0519] In some cases, an antibody provided herein binds to SLAMF7. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 903, 904, 905, 906, 907, and 908, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 903, 904, 905, 906, 907, and 908, respectively. In some embodiments, the anti-SLAMF7 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 909 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 910. [0520] In some cases, an antibody provided herein binds to C4.4a. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 911, 912, 913, 914, 915, and 916, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 911, 912, 913, 914, 915, and 916, respectively. In some embodiments, the anti-C4.4a antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 917 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 918. [0521] In some cases, an antibody provided herein binds to GCC. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 919, 920, 921, 922, 923, and 924, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 919, 920, 921, 922, 923, and 924, respectively. In some embodiments, the anti-GCC antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 925 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 926. [0522] In some cases, an antibody provided herein binds to Axl. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 927, 928, 929, 930, 931, and 932, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 927, 928, 929, 930, 931, and 932, respectively. In some embodiments, the anti-Axl antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 933 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 933. [0523] In some cases, an antibody provided herein binds to transmembrane glycoprotein NMB (gpNMB). In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 935, 936, 937, 938, 939, and 940, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 935, 936, 937, 938, 939, and 940, respectively. In some embodiments, the anti-gpNMB antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 941 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 942. In some embodiments, the anti-gpNMB antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 943 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 944. [0524] In some cases, an antibody provided herein binds to Prolactin receptor. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 945, 946, 947, 948, 949, and 950, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 945, 946, 947, 948, 949, and 950, respectively. In some embodiments, the anti- Prolactin receptor antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 951 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 952. [0525] In some cases, an antibody provided herein binds to FGFR2. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 953, 954, 955, 956, 957, and 958, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 953, 954, 955, 956, 957, and 958, respectively. In some embodiments, the anti-FGFR2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 959 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 960. [0526] In some cases, an antibody provided herein binds to CDCP1. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 961, 962, 963, 964, 965, and 966, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 969, 970, 971, 972, 973, and 974, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 961, 962, 963, 964, 965, and 966, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 969, 970, 971, 972, 973, and 974, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 977, 978, 979, 980, 981, and 982, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 977, 978, 979, 980, 981, and 982, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 985, 986, 987, 988, 989, and 990, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 985, 986, 987, 988, 989, and 990, respectively. In some embodiments, the anti-CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 967 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 968. In some embodiments, the anti-CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 975 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 976. In some embodiments, the anti- CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 983 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 984. In some embodiments, the anti-CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 991 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 992. [0527] In some cases, an antibody provided herein binds to ASCT2. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 997, 998, 999, 1000, 1001, and 1002, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 997, 998, 999, 1000, 1001, and 1002, respectively. In some embodiments, the anti-ASCT2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 993 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 994. In some embodiments, the anti-ASCT2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 995 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 996. In some embodiments, the anti-ASCT2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1003 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1004. [0528] In some cases, an antibody provided herein binds to CD123. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1005, 1006, 1007, 1008, 1009, and 1010, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1005, 1006, 1007, 1008, 1009, and 1010, respectively. In some embodiments, the anti-CD123 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1011 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1012. [0529] In some cases, an antibody provided herein binds to GPC3. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1013, 1014, 1015, 1016, 1017, and 1018 respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1013, 1014, 1015, 1016, 1017, and 1018, respectively. In some embodiments, the anti-TIGIT antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1027 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1028. [0530] In some cases, an antibody provided herein binds to TIGIT. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively. In some embodiments, the anti-BCMA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1043 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1044. [0531] In some cases, an antibody provided herein binds to CD33. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1029, 1030, 1031, 1032, 1033, and 1034, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1029, 1030, 1031, 1032, 1033, and 1034, respectively. In some embodiments, the anti-CD33 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1035 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1036. [0532] In some cases, an antibody provided herein binds to BCMA. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1037, 1038, 1039, 1040, 1041, and 1042, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1037, 1038, 1039, 1040, 1041, and 1042, respectively. In some embodiments, the anti-BCMA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1043 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1044. Ligand-Drug Conjugate compounds of compound 3.1 [0533] In some embodiments, provided is a compound 3.1,
Figure imgf000214_0001
wherein L is a ligand (e.g., an antibody) that targets an antigen selected from the group consisting of ADAM12 (e.g., Catalog #14139-1-AP); ADAM9 (e.g., IMGC936); AFP (e.g., ThermoFisher Catalog #PA5-25959); AGR2 (e.g., ThermoFisher Catalog #PA5-34517); AKAP-4 (e.g., Catalog #PA5-52230); ALK (e.g., DLX521); ALPP (e.g., Catalog #MA5- 15652); ALPPL2 (e.g., Catalog #PA5-22336); AMHR2 (e.g., ThermoFisher Catalog #PA5- 13902); androgen receptor (e.g., ThermoFisher Catalog #MA5-13426); ANTXR1 (e.g., Catalog #MA1-91702); ANXA1 (e.g., Catalog #71-3400); ARTN (e.g., ThermoFisher Catalog #PA5-47063); ASCT2 (e.g., idactamab); Axl (e.g., BA3011; tilvestamab); B7-DC (e.g., Catalog #PA5-20344); B7-H3 (e.g., enoblituzumab, omburtamab, MGD009, MGC018, DS-7300); B7-H4 (e.g., Catalog #14-5949-82); B7-H6 (e.g., Catalog #12-6526-42); B7-H7; BAFF-R (e.g., Catalog #14-9117-82); BCMA; BCR-ABL; BMPR2; BORIS; C4.4a; CanAg; C5 complement (e.g., BCD-148; CAN106); CA-125; CA19-9 (e.g., AbGn-7; MVT-5873); CA9 (e.g., girentuximab); CALCR (see, e.g., International Publication No. WO 2015077826); CAMPATH-1 (e.g., alemtuzumab; ALLO-647; ANT1034); carcinoembryonic antigen (e.g., arcitumomab; cergutuzumab; amunaleukin; labetuzumab); CCNB1; CD112 (see, e.g., U.S. Publication No. 20100008928); CD115 (e.g., axatilimab; cabiralizumab; emactuzumab); CD123 (e.g., BAY-943; CSL360); CD137 (e.g., ADG106; CTX-471); CD138; CD142; CD166; CD147 (e.g., gavilimomab; metuzumab); CD155 (e.g., U.S. Publication No. 2018/0251548); CD19 (e.g., ALLO-501); CD20 (e.g., divozilimab; ibritumomab tiuxetan); CD24 (see, e.g., U.S. Patent No. 8,614,301); CD244 (e.g., R&D AF1039); CD247 (e.g., AFM15); CD27 (e.g., varlilumab); CD274 (e.g., adebrelimab; atezolizumab; garivulimab); CD3 (e.g., otelixizumab; visilizumab); CD30 (e.g., iratumumab); CD33 (e.g., lintuzumab; BI 836858; AMG 673); CD288; CD352 (e.g., SGN-CD352A); CD37 (e.g., lilotomab; GEN3009); CD38 (e.g., felzartamab; AMG 424); CD3D; CD3E (e.g., foralumab; teplizumab); CD3G; CD45 (e.g., apamistamab); CD47 (e.g., letaplimab; magrolimab); CD48 (e.g., SGN-CD48A); CD5 (e.g., MAT 304; zolimomab aritox); CD56; CD59; CD70 (e.g., cusatuzumab); CD74 (e.g., milatuzumab); CD79A (see, e.g., International Publication No. WO 2020252110); CD79b; CD96; CD97; CD-262 (e.g., tigatuzumab); CDCP1 (e.g., RG7287); CDH17 (see, e.g., International Publication No. WO 2018115231); CDH3 (e.g., PCA062); CDH6 (e.g., HKT288); CEACAM1; CEACAM5; CEACAM6; CLDN1 (e.g., INSERM anti-Claudin-1); CLDN16; CLDN18.1 (e.g., zolbetuximab); CLDN18.2 (e.g., zolbetuximab); CLDN19; CLDN2 (see, e.g., International Publication No. WO 2018123949); CLEC12A (e.g., tepoditamab); CS1; CLPTM1L; CSPG4 (e.g., U.S. Patent No. 10,822,427); CXCR4 (e.g., ulocuplumab); CYP1B1; c-Met; DCLK1 (see, e.g., International Publication No. WO 2018222675); DDR1; de2-7 EGFR (e.g., MAb 806); DLL-3; DPEP1; DPEP3; DPP4; DR4 (e.g., mapatumumab); DSG2 (see, e.g., U.S. Patent No. 10,836,823); EGF; EGFR; endosialin (e.g., ontuxizumab); ENPP1; EPCAM (e.g., adecatumumab); EPHA receptors; EPHA2; ERBB2 (e.g., trastuzumab); ERBB3; ERVMER34_1; ETV6-AML (e.g., Catalog #PA5-81865); FAS; FasL; Fas-related antigen 1; FBP; FGFR1 (e.g., RG7992); FGFR2 (e.g., aprutumab); FGFR3 (e.g., vofatamab); FGFR4 (e.g., MM-161); FLT3 (e.g., 4G8SDIEM); FN; FN1; FOLR1 (e.g., farletuzumab); FRa; FSHR; FucGM1 (e.g., BMS-986012); FZD5; FZD8; G250; GAGE; GCC; GD2 (e.g., dinutuximab); GD3 (e.g., mitumomab); GITR (e.g., ragifilimab); GloboH; GM2 (e.g., BIW- 8962); GM3 (e.g., racotumomab); gp100; GPA33 (e.g., KRN330); GPC3 (e.g., codrituzumab); gpNMB (e.g., glembatumumab); GPR87; GUCY2C (e.g., indusatumab); HAS3; HAVCR2; HLA-E; HLA-F; HLA-G (e.g., TTX-080); HPV E6 E7; hTERT; ICAM1; IDO1; IFNAR1 (e.g., faralimomab); IFNAR2; IL13Ra2; IL1RAP (e.g., nidanilimab); IL-21R (e.g., PF-05230900); IL-5R (e.g., benralizumab); ITGAV (e.g., abituzumab); ITGB6; ITGB8; KISS1R; L1CAM (e.g., JCAR023); LAG-3 (e.g., encelimab); LAMP1; LCK; legumain; LMP2; LY6G6D (e.g., PA5-23303); LY9 (e.g., PA5-95601); LYPD1 (e.g., ThermoFisher Catalog #PA5-26749); MAD-CT-1; MAD-CT-2; MAGEA1 (e.g., Catalog #MA5-11338); MAGEA3 (e.g., ThermoFisher Catalog #60054-1-IG); MAGEA4 (e.g., Catalog #MA5- 26117); MAGEC2 (e.g., ThermoFisher Catalog #PA5-64010); MELTF (e.g., ThermoFisher Catalog #H00004241-M04A); MerTk (e.g., DS5MMER, Catalog #12-5751-82); a metalloproteinase; MFSD13A; MICA (e.g., 1E2C8, Catalog #66384-1-IG); MICB (e.g., Catalog #MA5-29422); Mincle (e.g., OTI2A8, Catalog #TA505101); MLANA (e.g., Catalog #MA5-15237); ML-IAP (e.g., 88C570, ThermoFisher Catalog #40958); MSLN (e.g., 5B2, Catalog #MA5-11918); MUC1 (e.g., MH1 (CT2), ThermoFisher Catalog #MA5-11202); MUC5AC (e.g., 45M1, Catalog #MA5-12178); MYCN (e.g., NCM-II 100, ThermoFisher Catalog #MA1-170); NA17; NCAM1 (e.g., ThermoFisher Catalog #MA5-11563); Nectin-4 (e.g., enfortumab); NOX1 (e.g., Catalog #PA5-103220); NT5E (e.g., 7G2, ThermoFisher Catalog #41-0200); NY-BR-1 (e.g., NY-BR-1 No. 2, Catalog #MA5-12645); NY-ESO-1 (e.g., E978m, Catalog #35-6200); OX40 (e.g., ABM193); OY-TES1; p53; p53mutant; PAP; PAX3 (e.g., GT1210, ThermoFisher Catalog #MA5-31583); PAX5; PDGFR-B (e.g., rinucumab); PDPN (e.g., ThermoFisher Catalog #14-5381-82); PLAVl; PMSA; polysialic acid (see, e.g., Watzlawik et al. J Nat Sci. 2015; 1(8):e141); PR1; PROM1 (e.g., Catalog #14- 1331-82); PSA (e.g., ThermoFisher Catalog #PA1-38514; Daniels-Wells et al. BMC Cancer 2013; 13:195); PSCA (e.g., AGS-1C4D4); PSMA (e.g., BAY 2315497); PTK7 (e.g., cofetuzumab); PVRIG; Ras mutant (e.g., Shin et al. Sci Adv. 2020; 6(3):eaay2174); RET (e.g., WO2020210551); RGS5 (e.g., TF-TA503075); RhoC (e.g., ThermoFisher Catalog PA5-77866); ROR1 (e.g., cirmtuzumab); ROR2 (e.g., BA3021); ROS1 (e.g., WO 2019107671); Sarcoma translocation breakpoints; SART3 (e.g., TF 18025-1-AP); Sialyl- Thomsen-nouveau-antigen (e.g., Eavarone et al. PLoS One. 2018; 13(7): e0201314); Siglecs 1-16 (see, e.g., Angata et al. Trends Pharmacol Sci. 2015; 36(10): 645–660); SIRPa (e.g., Catalog #17-1729-42); SIRPg (e.g., PA5-104381); SIT1 (e.g., PA5-53825); SLAMF7 (e.g., elotuzumab); SLC10A2 (e.g., ThermoFisher Catalog #PA5-18990); SLC12A2 (e.g., ThermoFisher Catalog #13884-1-AP); SLC17A2 (e.g., ThermoFisher Catalog #PA5- 106752); SLC38A1 (e.g., ThermoFisher Catalog #12039-1-AP); SLC39A5 (e.g., ThermoFisher Catalog #MA5-27260); SLC39A6 (e.g., ladiratuzumab); SLC44A4 (e.g., ASG-5ME); SLC6A15 (e.g., ThermoFisher Catalog #PA5-52586); SLC6A6 (e.g., ThermoFisher Catalog #PA5-53431); SLC7A11 (e.g., ThermoFisher Catalog #PA1-16893); SLC7A5; sLe; SLITRK6 (e.g., sirtratumab); Sperm protein 17 (e.g., BS-5754R); SSX2 (e.g., ThermoFisher Catalog #MA5-24971); survivin (e.g., PA1-16836); TACSTD2 (e.g., PA5- 47074); TAG-72 (e.g., MA1-25956); tenascin; TF (e.g., tisotumab); Tie3; TLR2/4/1 (e.g., tomaralimab); TM4SF5 (e.g., 18239-1-AP); TMEM132A (e.g., Catalog #PA5-62524); TMEM40 (e.g., PA5-60636); TMPRSS11D (e.g., PA5-30927); Tn; TNFRSF12 (e.g., BAY- 356); TRAIL (e.g., Catalog #12-9927-42); TRAIL1; TRP-2 (e.g., PA5-52736); ULBP1/2/3/4/5/6 (e.g., PA5-82302); uPAR (e.g., ATN-658); UPK1B (e.g., ThermoFisher Catalog #PA5-56863); UPK2 (e.g., ThermoFisher Catalog #PA5-60318); UPK3B (e.g., ThermoFisher Catalog #PA5-52696); VEGF (e.g., GNR-011); VEGFR2 (e.g., gentuximab); VSIR (e.g., ThermoFisher Catalog #PA5-52493); WT1 (e.g., ThermoFisher Catalog #MA5- 32215); and XAGE1 (e.g., ThermoFisher Catalog #PA5-46413). [0534] Also provided herein is a compound 3.1, wherein L is a ligand (e.g., an antibody) that targets an antigen selected from the group consisting of Axl (e.g., BA3011; tilvestamab); B7-1 (e.g., galiximab); B7-2 (e.g., Catalog #12-0862-82); B7-DC (e.g., Catalog #PA5- 20344); B7-H3 (e.g., enoblituzumab, omburtamab, MGD009, MGC018, DS-7300); B7-H4 (e.g., Catalog #14-5949-82); B7-H6 (e.g., Catalog #12-6526-42); B7-H7; BAFF-R (e.g., Catalog #14-9117-82); BCMA; C5 complement (e.g., BCD-148; CAN106); CCR4 (e.g., AT008; mogamulizumab-kpkc); CCR8 (e.g., JTX-1811); CD112 (see, e.g., U.S. Publication No. 20100008928); CD115 (e.g., axatilimab; cabiralizumab; emactuzumab); CD123 (e.g., BAY-943; CSL360); CD137 (e.g., ADG106; CTX-471); CD155 (e.g., U.S. Publication No. 2018/0251548); CD163 (e.g., TBI 304H); CD19 (e.g., ALLO-501); CD2 (e.g., BTI-322; siplizumab); CD20 (e.g., divozilimab; ibritumomab); CD24 (see, e.g., U.S. Patent No. 8,614,301); CD244 (e.g., R&D AF1039); CD247 (e.g., AFM15); CD25 (e.g., basiliximab); CD27 (e.g., varlilumab); CD274 (e.g., adebrelimab; atezolizumab; garivulimab); CD278 (e.g., feladilimab; vopratelimab); CD28 (e.g., REGN5668); CD3 (e.g., otelixizumab; visilizumab); CD30 (e.g., iratumumab); CD30L (see, e.g., U.S. Patent No. 9,926,373); CD32 (e.g., mAb 2B6); CD33 (e.g., lintuzumab; BI 836858; AMG 673); CD352 (e.g., SGN- CD352A); CD37 (e.g., lilotomab; GEN3009); CD38 (e.g., felzartamab; AMG 424); CD3D; CD3E (e.g., foralumab; teplizumab); CD3G; CD40 (e.g., dacetuzumab; lucatumumab); CD44 (e.g., RG7356); CD45 (e.g., apamistamab); CD47 (e.g., letaplimab; magrolimab); CD48 (e.g., SGN-CD48A); CD5 (e.g., MAT 304; zolimomab aritox); CD51; CD70 (e.g., cusatuzumab); CD74 (e.g., milatuzumab); CD79A (see, e.g., International Publication No. WO 2020252110); CD83 (e.g., CBT004); CD97; CD262 (e.g., tigatuzumab); CLEC12A (e.g., tepoditamab); CTLA4 (e.g., ipilimumab); CXCR4 (e.g., ulocuplumab); DCIR; DCSIGN (see, e.g., International Publication No. WO 2018134389); Dectin1 (see, e.g., U.S. Patent No. 9,045,542); Dectin2 (e.g., ThermoFisher Catalog #MA5-16250); DR4 (e.g., mapatumumab); endosialin (e.g., ontuxizumab); FasL; FLT3 (e.g., 4G8SDIEM); GITR (e.g., ragifilimab); HAVCR2; HER2; HER3; HLA-DR; HLA-E; HLA-F; HLA-G (e.g., TTX-080); ICAM1; IDO1; IFNAR1 (e.g., faralimomab); IFNAR2; IGF-1R; IL1RAP (e.g., nidanilimab); IL-21R (e.g., PF-05230900); IL-5R (e.g., benralizumab); Integrin αvβ6; LAG-3 (e.g., encelimab); LAMP1; LAYN; LCK; LILRB2; LILRB4; MerTk (e.g., DS5MMER, Catalog #12-5751-82); Mesothelin; MICA (e.g., 1E2C8, Catalog #66384-1-IG); MICB (e.g., Catalog #MA5-29422); MICA; Mincle (e.g., OTI2A8, Catalog #TA505101); MRC1 (e.g., ThermoFisher Catalog #12-2061-82); MUC1; Muc16; NcaPi2B; Nectin-4; OX40 (e.g., ABM193); PD-1 (e.g., balstilimab; budigalimab; geptanolimab); PD-L1; Prolactin receptor; PTK7; PVRIG; ROR-1; Sialyl-Thomsen-nouveau-antigen (e.g., Eavarone et al. PLoS One, 2018; 13(7): e0201314); Siglecs 1-16 (see, e.g., Angata et al. Trends Pharmacol Sci. 2015; 36(10): 645–660); ); SIRPa (e.g., Catalog #17-1729-42); SIRPg (e.g., PA5-104381); SIT1 (e.g., PA5-53825); SLAMF7 (e.g., elotuzumab); SLTRK6; STEAP1; TIGIT (e.g., etigilimab); TLR2/4/1 (e.g., tomaralimab); Trem2 (e.g., PY314); TROP2; Tyrol; ULBP1/2/3/4/5/6 (e.g., PA5-82302); uPAR (e.g., ATN-658); VSIR (e.g., ThermoFisher Catalog #PA5-52493); and ZIP6 (Anti- Integrin αvβ6). (v) Heavy Chain and Light Chain Variable Regions in a compound 3.1 [0535] In some embodiments, the L moiety of compound 3.1 is a ligand (e.g., an antibody or fragment thereof) that targets ADAM9, ASCT2, Axl, B7-H3, B7H4, BCMA, BCMA, C4.4a, CanAg, CD123, CD138, CD142, CD166, CD19, CD20, CD228, CD25, CD30, CD33, CD352, CD38, CD48, CD56, CD59, CD70, CD74, CD79b, CDCP1, CEACAM5, Claudin- 18.2, c-Met, gpNMB, CS1, DLL-3, DPEP-3, EGFR, EpCAM, EphA2, FGFR2, FRa, GCC, gpA33, GPC3, Integrin αvβ6 , h2A2, H2G12/STn, HER2, HER3, ZIP6, IGF-1R, IL1Rap, ITGav/CD51, Mesothelin, MICA, MUC-1, Muc16, NaPi2B, Nectin-4, PD-L1, Prolactin receptor, PTK7, ROR-1, SLAMF7, SLTRK6, STEAP1, TIGIT, or TROP2. [0536] In some embodiments, the L moiety of compound 3.1 comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, and wherein: the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 44 and the second sequence is SEQ ID NO: 45; the first sequence is SEQ ID NO: 55 and the second sequence is SEQ ID NO: 56; the first sequence is SEQ ID NO: 69 and the second sequence is SEQ ID NO: 70; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121 and the second sequence is SEQ ID NO: 122; the first sequence is SEQ ID NO: 129 and the second sequence is SEQ ID NO: 130; the first sequence is SEQ ID NO: 137 and the second sequence is SEQ ID NO: 138; the first sequence is SEQ ID NO: 153 and the second sequence is SEQ ID NO: 154; the first sequence is SEQ ID NO: 161 and the second sequence is SEQ ID NO: 162; the first sequence is SEQ ID NO: 169 and the second sequence is SEQ ID NO: 170; the first sequence is SEQ ID NO: 177 and the second sequence is SEQ ID NO: 178; the first sequence is SEQ ID NO: 185 and the second sequence is SEQ ID NO: 186; the first sequence is SEQ ID NO: 193 and the second sequence is SEQ ID NO: 194; the first sequence is SEQ ID NO: 201 and the second sequence is SEQ ID NO: 202; the first sequence is SEQ ID NO: 209 and the second sequence is SEQ ID NO: 210; the first sequence is SEQ ID NO: 217 and the second sequence is SEQ ID NO: 218; the first sequence is SEQ ID NO: 225 and the second sequence is SEQ ID NO: 226; the first sequence is SEQ ID NO: 233 and the second sequence is SEQ ID NO: 234; the first sequence is SEQ ID NO: 241 and the second sequence is SEQ ID NO: 242; the first sequence is SEQ ID NO: 249 and the second sequence is SEQ ID NO: 250; the first sequence is SEQ ID NO: 297 and the second sequence is SEQ ID NO: 298; the first sequence is SEQ ID NO: 307 and the second sequence is SEQ ID NO: 308; the first sequence is SEQ ID NO: 315 and the second sequence is SEQ ID NO: 316; the first sequence is SEQ ID NO: 323 and the second sequence is SEQ ID NO: 324; the first sequence is SEQ ID NO: 331 and the second sequence is SEQ ID NO: 332; the first sequence is SEQ ID NO: 339 and the second sequence is SEQ ID NO: 340; the first sequence is SEQ ID NO: 347 and the second sequence is SEQ ID NO: 348; the first sequence is SEQ ID NO: 355 and the second sequence is SEQ ID NO: 356; the first sequence is SEQ ID NO: 363 and the second sequence is SEQ ID NO: 364; the first sequence is SEQ ID NO: 371 and the second sequence is SEQ ID NO: 372; the first sequence is SEQ ID NO: 379 and the second sequence is SEQ ID NO: 380; the first sequence is SEQ ID NO: 387 and the second sequence is SEQ ID NO: 388; the first sequence is SEQ ID NO: 395 and the second sequence is SEQ ID NO: 396; the first sequence is SEQ ID NO: 403 and the second sequence is SEQ ID NO: 404; the first sequence is SEQ ID NO: 411 and the second sequence is SEQ ID NO: 412; the first sequence is SEQ ID NO: 419 and the second sequence is SEQ ID NO: 420; the first sequence is SEQ ID NO: 427 and the second sequence is SEQ ID NO: 428; the first sequence is SEQ ID NO: 435 and the second sequence is SEQ ID NO: 436; the first sequence is SEQ ID NO: 443 and the second sequence is SEQ ID NO: 444; the first sequence is SEQ ID NO: 451 and the second sequence is SEQ ID NO: 452; the first sequence is SEQ ID NO: 459 and the second sequence is SEQ ID NO: 460; the first sequence is SEQ ID NO: 467 and the second sequence is SEQ ID NO: 468; the first sequence is SEQ ID NO: 475 and the second sequence is SEQ ID NO: 476; the first sequence is SEQ ID NO: 483 and the second sequence is SEQ ID NO: 484; the first sequence is SEQ ID NO: 491 and the second sequence is SEQ ID NO: 492; the first sequence is SEQ ID NO: 501 and the second sequence is SEQ ID NO: 502; the first sequence is SEQ ID NO: 509 and the second sequence is SEQ ID NO: 510; the first sequence is SEQ ID NO: 517 and the second sequence is SEQ ID NO: 518; the first sequence is SEQ ID NO: 525 and the second sequence is SEQ ID NO: 526; the first sequence is SEQ ID NO: 533 and the second sequence is SEQ ID NO: 534; the first sequence is SEQ ID NO: 541 and the second sequence is SEQ ID NO: 542; the first sequence is SEQ ID NO: 549 and the second sequence is SEQ ID NO: 550; the first sequence is SEQ ID NO: 557 and the second sequence is SEQ ID NO: 558; the first sequence is SEQ ID NO: 565 and the second sequence is SEQ ID NO: 566; the first sequence is SEQ ID NO: 574 and the second sequence is SEQ ID NO: 574; the first sequence is SEQ ID NO: 581 and the second sequence is SEQ ID NO: 582; the first sequence is SEQ ID NO: 589 and the second sequence is SEQ ID NO: 590; the first sequence is SEQ ID NO: 597 and the second sequence is SEQ ID NO: 598; the first sequence is SEQ ID NO: 605 and the second sequence is SEQ ID NO: 606; the first sequence is SEQ ID NO: 613 and the second sequence is SEQ ID NO: 614; the first sequence is SEQ ID NO: 621 and the second sequence is SEQ ID NO: 622; the first sequence is SEQ ID NO: 629 and the second sequence is SEQ ID NO: 630; the first sequence is SEQ ID NO: 637 and the second sequence is SEQ ID NO: 638; the first sequence is SEQ ID NO: 645 and the second sequence is SEQ ID NO: 646; the first sequence is SEQ ID NO: 653 and the second sequence is SEQ ID NO: 654; the first sequence is SEQ ID NO: 661 and the second sequence is SEQ ID NO: 662; the first sequence is SEQ ID NO: 669 and the second sequence is SEQ ID NO: 670; the first sequence is SEQ ID NO: 677 and the second sequence is SEQ ID NO: 678; the first sequence is SEQ ID NO: 685 and the second sequence is SEQ ID NO: 686; the first sequence is SEQ ID NO: 693 and the second sequence is SEQ ID NO: 694; the first sequence is SEQ ID NO: 701 and the second sequence is SEQ ID NO: 702; the first sequence is SEQ ID NO: 703 and the second sequence is SEQ ID NO: 704; the first sequence is SEQ ID NO: 711 and the second sequence is SEQ ID NO: 712; the first sequence is SEQ ID NO: 713 and the second sequence is SEQ ID NO: 714; the first sequence is SEQ ID NO: 715 and the second sequence is SEQ ID NO: 716; the first sequence is SEQ ID NO: 731 and the second sequence is SEQ ID NO: 732; the first sequence is SEQ ID NO: 739 and the second sequence is SEQ ID NO: 740; the first sequence is SEQ ID NO: 747 and the second sequence is SEQ ID NO: 748; the first sequence is SEQ ID NO: 755 and the second sequence is SEQ ID NO: 756; the first sequence is SEQ ID NO: 765 and the second sequence is SEQ ID NO: 766; the first sequence is SEQ ID NO: 773 and the second sequence is SEQ ID NO: 774; the first sequence is SEQ ID NO: 781 and the second sequence is SEQ ID NO: 782; the first sequence is SEQ ID NO: 789 and the second sequence is SEQ ID NO: 790; the first sequence is SEQ ID NO: 797 and the second sequence is SEQ ID NO: 798; the first sequence is SEQ ID NO: 805 and the second sequence is SEQ ID NO: 806; the first sequence is SEQ ID NO: 813 and the second sequence is SEQ ID NO: 814; the first sequence is SEQ ID NO: 821 and the second sequence is SEQ ID NO: 822; the first sequence is SEQ ID NO: 829 and the second sequence is SEQ ID NO: 830; the first sequence is SEQ ID NO: 837 and the second sequence is SEQ ID NO: 838; the first sequence is SEQ ID NO: 845 and the second sequence is SEQ ID NO: 846; the first sequence is SEQ ID NO: 853 and the second sequence is SEQ ID NO: 854; the first sequence is SEQ ID NO: 861 and the second sequence is SEQ ID NO: 862; the first sequence is SEQ ID NO: 869 and the second sequence is SEQ ID NO: 870; the first sequence is SEQ ID NO: 877 and the second sequence is SEQ ID NO: 878; the first sequence is SEQ ID NO: 885 and the second sequence is SEQ ID NO: 886; the first sequence is SEQ ID NO: 893 and the second sequence is SEQ ID NO: 894; the first sequence is SEQ ID NO: 900 and the second sequence is SEQ ID NO: 901; the first sequence is SEQ ID NO: 909 and the second sequence is SEQ ID NO: 910; the first sequence is SEQ ID NO: 917 and the second sequence is SEQ ID NO: 918; the first sequence is SEQ ID NO: 925 and the second sequence is SEQ ID NO: 926; the first sequence is SEQ ID NO: 933 and the second sequence is SEQ ID NO: 934; the first sequence is SEQ ID NO: 941 and the second sequence is SEQ ID NO: 942; the first sequence is SEQ ID NO: 943 and the second sequence is SEQ ID NO: 944; the first sequence is SEQ ID NO: 951 and the second sequence is SEQ ID NO: 952; the first sequence is SEQ ID NO: 959 and the second sequence is SEQ ID NO: 960; the first sequence is SEQ ID NO: 967 and the second sequence is SEQ ID NO: 968; the first sequence is SEQ ID NO: 975 and the second sequence is SEQ ID NO: 976; the first sequence is SEQ ID NO: 983 and the second sequence is SEQ ID NO: 984; the first sequence is SEQ ID NO: 991 and the second sequence is SEQ ID NO: 992; the first sequence is SEQ ID NO: 993 and the second sequence is SEQ ID NO: 994; the first sequence is SEQ ID NO: 995 and the second sequence is SEQ ID NO: 996; the first sequence is SEQ ID NO: 1003 and the second sequence is SEQ ID NO: 1004; the first sequence is SEQ ID NO: 1011 and the second sequence is SEQ ID NO: 1012; the first sequence is SEQ ID NO: 1019 and the second sequence is SEQ ID NO: 1020; the first sequence is SEQ ID NO: 1027 and the second sequence is SEQ ID NO: 1028; the first sequence is SEQ ID NO: 1035 and 1036; or the first sequence is SEQ ID NO: 1043 and the second sequence is SEQ ID NO: 1044. [0537] In some embodiments, the L moiety of compound 3.1 comprises an antibody that targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, and TIGIT. For example, in some cases, the antibody comprises a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO:113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121 and the second sequence is SEQ ID NO: 122; the first sequence is SEQ ID NO: 129 and the second sequence is SEQ ID NO: 130; the first sequence is SEQ ID NO: 137 and the second sequence is SEQ ID NO: 138; the first sequence is SEQ ID NO: 153 and the second sequence is SEQ ID NO: 154; the first sequence is SEQ ID NO: 161 and the second sequence is SEQ ID NO: 162; the first sequence is SEQ ID NO: 169 and the second sequence is SEQ ID NO: 170; the first sequence is SEQ ID NO: 177 and the second sequence is SEQ ID NO: 178; the first sequence is SEQ ID NO: 185 and the second sequence is SEQ ID NO: 186; the first sequence is SEQ ID NO: 193 and the second sequence is SEQ ID NO: 194; the first sequence is SEQ ID NO: 201 and the second sequence is SEQ ID NO: 202; the first sequence is SEQ ID NO: 209 and the second sequence is SEQ ID NO: 210; the first sequence is SEQ ID NO: 217 and the second sequence is SEQ ID NO: 218; the first sequence is SEQ ID NO: 225 and the second sequence is SEQ ID NO: 226; the first sequence is SEQ ID NO: 233 and the second sequence is SEQ ID NO: 234; the first sequence is SEQ ID NO: 241 and the second sequence is SEQ ID NO: 242; the first sequence is SEQ ID NO: 249 and the second sequence is SEQ ID NO: 250; the first sequence is SEQ ID NO: 629 and the second sequence is SEQ ID NO: 630; the first sequence is SEQ ID NO: 637 and the second sequence is SEQ ID NO: 638; the first sequence is SEQ ID NO: 645 and the second sequence is SEQ ID NO: 646; the first sequence is SEQ ID NO: 653 and the second sequence is SEQ ID NO: 654; the first sequence is SEQ ID NO: 661 and the second sequence is SEQ ID NO: 662; the first sequence is SEQ ID NO: 669 and the second sequence is SEQ ID NO: 670; the first sequence is SEQ ID NO: 677 and the second sequence is SEQ ID NO: 678; the first sequence is SEQ ID NO: 685 and the second sequence is SEQ ID NO: 686; the first sequence is SEQ ID NO: 693 and the second sequence is SEQ ID NO: 694; the first sequence is SEQ ID NO: 701 and the second sequence is SEQ ID NO: 702; the first sequence is SEQ ID NO: 703 and the second sequence is SEQ ID NO: 704; the first sequence is SEQ ID NO: 711 and the second sequence is SEQ ID NO: 712; the first sequence is SEQ ID NO: 713 and the second sequence is SEQ ID NO: 714; the first sequence is SEQ ID NO: 715 and the second sequence is SEQ ID NO: 716; or the first sequence is SEQ ID NO: 1027 and the second sequence is SEQ ID NO: 1028. [0538] In some embodiments, the L moiety of compound 3.1 comprises an antibody comprising a heavy chain variable region having at least 80% sequence identity to a first sequence and a light chain variable region having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20; the first sequence is SEQ ID NO: 83 and the second sequence is SEQ ID NO: 84; the first sequence is SEQ ID NO: 97 and the second sequence is SEQ ID NO: 98; the first sequence is SEQ ID NO: 105 and the second sequence is SEQ ID NO: 106; the first sequence is SEQ ID NO: 113 and the second sequence is SEQ ID NO: 114; the first sequence is SEQ ID NO: 121 and the second sequence is SEQ ID NO: 122; the first sequence is SEQ ID NO: 129 and the second sequence is SEQ ID NO: 130; the first sequence is SEQ ID NO: 137 and the second sequence is SEQ ID NO: 138; the first sequence is SEQ ID NO: 153 and the second sequence is SEQ ID NO: 154; the first sequence is SEQ ID NO: 161 and the second sequence is SEQ ID NO: 162; the first sequence is SEQ ID NO: 169 and the second sequence is SEQ ID NO: 170; the first sequence is SEQ ID NO: 177 and the second sequence is SEQ ID NO: 178; the first sequence is SEQ ID NO: 185 and the second sequence is SEQ ID NO: 186; the first sequence is SEQ ID NO: 193 and the second sequence is SEQ ID NO: 194; the first sequence is SEQ ID NO: 201 and the second sequence is SEQ ID NO: 202; the first sequence is SEQ ID NO: 209 and the second sequence is SEQ ID NO: 210; the first sequence is SEQ ID NO: 217 and the second sequence is SEQ ID NO: 218; the first sequence is SEQ ID NO: 225 and the second sequence is SEQ ID NO: 226; the first sequence is SEQ ID NO: 233 and the second sequence is SEQ ID NO: 234; the first sequence is SEQ ID NO: 241 and the second sequence is SEQ ID NO: 242; the first sequence is SEQ ID NO: 249 and the second sequence is SEQ ID NO: 250; or the first sequence is SEQ ID NO: 1027 and the second sequence is SEQ ID NO: 1028. In some cases, the first sequence is SEQ ID NO: 19 and the second sequence is SEQ ID NO: 20. [0539] In some embodiments, the heavy chain variable region of the L moiety of compound 3.1 has at least 85% sequence identity to the first sequence and the light chain variable region has at least 85% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 90% sequence identity to the first sequence and the light chain variable region has at least 90% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 95% sequence identity to the first sequence and the light chain variable region has at least 95% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 98% sequence identity to the first sequence and the light chain variable region has at least 98% sequence identity to the second sequence. In some cases, the heavy chain variable region has at least 99% sequence identity to the first sequence and the light chain variable region has at least 99% sequence identity to the second sequence. In some cases, the heavy chain variable region comprises the first sequence and the light chain variable region comprises the second sequence. (vi) Heavy and Light Chains [0540] In some embodiments, the L moiety of compound 3.1 comprises an antibody comprising a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 46 and the second sequence is SEQ ID NO: 48; the first sequence is SEQ ID NO: 47 and the second sequence is SEQ ID NO: 48; the first sequence is SEQ ID NO: 57 and the second sequence is SEQ ID NO: 59; the first sequence is SEQ ID NO: 58 and the second sequence is SEQ ID NO: 59; the first sequence is SEQ ID NO: 60 and the second sequence is SEQ ID NO: 62; the first sequence is SEQ ID NO: 61 and the second sequence is SEQ ID NO: 62; the first sequence is SEQ ID NO: 71 and the second sequence is SEQ ID NO: 73; the first sequence is SEQ ID NO: 72 and the second sequence is SEQ ID NO: 73; the first sequence is SEQ ID NO: 74 and the second sequence is SEQ ID NO: 76; the first sequence is SEQ ID NO: 75 and the second sequence is SEQ ID NO: 76; the first sequence is SEQ ID NO: 85 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 86 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 88 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 89 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 251 and the second sequence is SEQ ID NO: 252; the first sequence is SEQ ID NO: 253 and the second sequence is SEQ ID NO: 254; the first sequence is SEQ ID NO: 255 and the second sequence is SEQ ID NO: 256; the first sequence is SEQ ID NO: 257 and the second sequence is SEQ ID NO: 258; the first sequence is SEQ ID NO: 259 and the second sequence is SEQ ID NO: 260; the first sequence is SEQ ID NO: 261 and the second sequence is SEQ ID NO: 262; the first sequence is SEQ ID NO: 263 and the second sequence is SEQ ID NO: 264; the first sequence is SEQ ID NO: 265 and the second sequence is SEQ ID NO: 266; the first sequence is SEQ ID NO: 267 and the second sequence is SEQ ID NO: 268; the first sequence is SEQ ID NO: 269 and the second sequence is SEQ ID NO: 270; the first sequence is SEQ ID NO: 271 and the second sequence is SEQ ID NO: 272; the first sequence is SEQ ID NO: 273 and the second sequence is SEQ ID NO: 274; the first sequence is SEQ ID NO: 275 and the second sequence is SEQ ID NO: 276; the first sequence is SEQ ID NO: 277 and the second sequence is SEQ ID NO: 278; the first sequence is SEQ ID NO: 279 and the second sequence is SEQ ID NO: 280; the first sequence is SEQ ID NO: 281 and the second sequence is SEQ ID NO: 282; the first sequence is SEQ ID NO: 283 and the second sequence is SEQ ID NO: 284; the first sequence is SEQ ID NO: 285 and the second sequence is SEQ ID NO: 286; the first sequence is SEQ ID NO: 287 and the second sequence is SEQ ID NO: 288; the first sequence is SEQ ID NO: 289 and the second sequence is SEQ ID NO: 290; the first sequence is SEQ ID NO: 299 and the second sequence is SEQ ID NO: 300; the first sequence is SEQ ID NO: 493 and the second sequence is SEQ ID NO: 494; the first sequence is SEQ ID NO: 717 and the second sequence is SEQ ID NO: 718; the first sequence is SEQ ID NO: 719 and the second sequence is SEQ ID NO: 720; the first sequence is SEQ ID NO: 721 and the second sequence is SEQ ID NO: 722; the first sequence is SEQ ID NO: 723 and the second sequence is SEQ ID NO: 724; or the first sequence is SEQ ID NO: 757 and the second sequence is SEQ ID NO: 758. [0541] In some embodiments, the L moiety of compound 3.1 comprises an antibody comprising a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 85 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 86 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 88 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 89 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 251 and the second sequence is SEQ ID NO: 252; the first sequence is SEQ ID NO: 253 and the second sequence is SEQ ID NO: 254; the first sequence is SEQ ID NO: 255 and the second sequence is SEQ ID NO: 256; the first sequence is SEQ ID NO: 257 and the second sequence is SEQ ID NO: 258; the first sequence is SEQ ID NO: 259 and the second sequence is SEQ ID NO: 260; the first sequence is SEQ ID NO: 261 and the second sequence is SEQ ID NO: 262; the first sequence is SEQ ID NO: 263 and the second sequence is SEQ ID NO: 264; the first sequence is SEQ ID NO: 265 and the second sequence is SEQ ID NO: 266; the first sequence is SEQ ID NO: 267 and the second sequence is SEQ ID NO: 268; the first sequence is SEQ ID NO: 269 and the second sequence is SEQ ID NO: 270; the first sequence is SEQ ID NO: 271 and the second sequence is SEQ ID NO: 272; the first sequence is SEQ ID NO: 273 and the second sequence is SEQ ID NO: 274; the first sequence is SEQ ID NO: 275 and the second sequence is SEQ ID NO: 276; the first sequence is SEQ ID NO: 277 and the second sequence is SEQ ID NO: 278; the first sequence is SEQ ID NO: 279 and the second sequence is SEQ ID NO: 280; the first sequence is SEQ ID NO: 281 and the second sequence is SEQ ID NO: 282; the first sequence is SEQ ID NO: 283 and the second sequence is SEQ ID NO: 284; the first sequence is SEQ ID NO: 285 and the second sequence is SEQ ID NO: 286; the first sequence is SEQ ID NO: 287 and the second sequence is SEQ ID NO: 288; the first sequence is SEQ ID NO: 289 and the second sequence is SEQ ID NO: 290; the first sequence is SEQ ID NO: 717 and the second sequence is SEQ ID NO: 718; the first sequence is SEQ ID NO: 719 and the second sequence is SEQ ID NO: 720; the first sequence is SEQ ID NO: 721 and the second sequence is SEQ ID NO: 722; or the first sequence is SEQ ID NO: 723 and the second sequence is SEQ ID NO: 724. [0542] In some embodiments, the L moiety of compound 3.1 comprises an antibody comprising a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 85 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 86 and the second sequence is SEQ ID NO: 87; the first sequence is SEQ ID NO: 88 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 89 and the second sequence is SEQ ID NO: 90; the first sequence is SEQ ID NO: 251 and the second sequence is SEQ ID NO: 252; the first sequence is SEQ ID NO: 253 and the second sequence is SEQ ID NO: 254; the first sequence is SEQ ID NO: 255 and the second sequence is SEQ ID NO: 256; the first sequence is SEQ ID NO: 257 and the second sequence is SEQ ID NO: 258; the first sequence is SEQ ID NO: 259 and the second sequence is SEQ ID NO: 260; the first sequence is SEQ ID NO: 261 and the second sequence is SEQ ID NO: 262; the first sequence is SEQ ID NO: 263 and the second sequence is SEQ ID NO: 264; the first sequence is SEQ ID NO: 265 and the second sequence is SEQ ID NO: 266; the first sequence is SEQ ID NO: 267 and the second sequence is SEQ ID NO: 268; the first sequence is SEQ ID NO: 269 and the second sequence is SEQ ID NO: 270; the first sequence is SEQ ID NO: 271 and the second sequence is SEQ ID NO: 272; the first sequence is SEQ ID NO: 273 and the second sequence is SEQ ID NO: 274; the first sequence is SEQ ID NO: 275 and the second sequence is SEQ ID NO: 276; the first sequence is SEQ ID NO: 277 and the second sequence is SEQ ID NO: 278; the first sequence is SEQ ID NO: 279 and the second sequence is SEQ ID NO: 280; the first sequence is SEQ ID NO: 281 and the second sequence is SEQ ID NO: 282; the first sequence is SEQ ID NO: 283 and the second sequence is SEQ ID NO: 284; the first sequence is SEQ ID NO: 285 and the second sequence is SEQ ID NO: 286; the first sequence is SEQ ID NO: 287 and the second sequence is SEQ ID NO: 288; or the first sequence is SEQ ID NO: 289 and the second sequence is SEQ ID NO: 290. [0543] In some embodiments, the L moiety of compound 3.1 comprises an antibody comprising a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 1 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 2 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 3 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5; the first sequence is SEQ ID NO: 6 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 7 and the second sequence is SEQ ID NO: 10; the first sequence is SEQ ID NO: 8 and the second sequence is SEQ ID NO: 10; or the first sequence is SEQ ID NO: 9 and the second sequence is SEQ ID NO: 10. [0544] In some embodiments, the L moiety of is an antibody comprising a heavy chain having at least 80% sequence identity to a first sequence and a light chain having at least 80% sequence identity to a second sequence, wherein: the first sequence is SEQ ID NO: 3 or SEQ ID NO: 4 and the second sequence is SEQ ID NO: 5. [0545] In some embodiments, the L moiety of compound 3.1 comprises a heavy chain with at least 85% sequence identity to the first sequence and the light chain has at least 85% sequence identity to the second sequence. In some cases, the heavy chain has at least 90% sequence identity to the first sequence and the light chain has at least 90% sequence identity to the second sequence. In some cases, the heavy chain has at least 95% sequence identity to the first sequence and the light chain has at least 95% sequence identity to the second sequence. In some cases, the heavy chain has at least 98% sequence identity to the first sequence and the light chain has at least 98% sequence identity to the second sequence. In some cases, the heavy chain has at least 99% sequence identity to the first sequence and the light chain has at least 99% sequence identity to the second sequence. In some cases, the heavy chain comprises the first sequence and the light chain comprises the second sequence. (vii) Complementarity-Determining Regions [0546] In some embodiments, the L moiety of compound 3.1 comprises an antibody comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising at least 80% sequence identity to: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively (i.e., CDR-H1 has at least 80% sequence identity to SEQ ID NO: 13, CDR-H2 has at least 80% sequence identity to SEQ ID NO: 14, CDR-H3 has at least 80% sequence identity to SEQ ID NO: 15, CDR-L1 has at least 80% sequence identity to SEQ ID NO: 16, CDR-L2 has at least 80% sequence identity to SEQ ID NO: 17, and CDR-L3 has at least 80% sequence identity to SEQ ID NO: 18); SEQ ID NO: 21, 22, 23, 24, 25, and 26, respectively; SEQ ID NO: 38, 39, 40, 41, 42, and 43, respectively; SEQ ID NO: 49, 50, 51, 52, 53, and 54, respectively; SEQ ID NO: 63, 64, 65, 66, 67, and 68, respectively; SEQ ID NO: 77, 78, 79, 80, 81, and 82, , respectively; SEQ ID NO: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NO: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NO: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NO: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NO: 123, 124, 125, 126, 127, and 128, respectively; SEQ ID NO: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NO: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NO: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NO: 155, 156, 157, 158, 159, and 160, respectively; SEQ ID NO: 163, 164, 165, 166, 167, and 168, respectively; SEQ ID NO: 171, 172, 173, 174, 175, and 176, respectively; SEQ ID NO: 179, 180, 181, 182, 183, and 184, respectively; SEQ ID NO: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NO: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NO: 203, 204, 205, 206, 207 and 208, respectively; SEQ ID NO: 211, 212, 213, 214, 215, and 216, respectively; SEQ ID NO: 219, 220, 221, 222, 223, and 224, respectively; SEQ ID NO: 227, 228, 229, 230, 231, and 232, respectively; SEQ ID NO: 235, 236, 237, 238, 239, and 240, respectively; SEQ ID NO: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NO: 291, 292, 293, 294, 295, and 296, respectively; SEQ ID NO: 301, 302, 303, 304, 305, and 306, respectively; SEQ ID NO: 309, 310, 311, 312, 313, and 314, respectively; SEQ ID NO: 317, 318, 319, 320, 321, and 322, respectively; SEQ ID NO: 325, 326, 327, 328, 329, and 330, respectively; SEQ ID NO: 333, 334, 335, 336, 337, and 338, respectively; SEQ ID NO: 341, 342, 343, 344, 345, and 346, respectively; SEQ ID NO: 349, 350, 351, 352, 353, and 354, respectively; SEQ ID NO: 357, 358, 359, 360, 361, and 362, respectively; SEQ ID NO: 365, 366, 367, 368, 369, and 370, respectively; SEQ ID NO: 373, 374, 375, 376, 377, and 378, respectively; SEQ ID NO: 381, 382, 383, 384, 385, and 386, respectively; SEQ ID NO: 389, 390, 391, 392, 393, and 394, respectively; SEQ ID NO: 397, 398, 399, 400, 401, and 402, respectively; SEQ ID NO: 405, 406, 407, 408, 409, and 410, respectively; SEQ ID NO: 413, 414, 415, 416, 417, and 418, respectively; SEQ ID NO: 421, 422, 423, 424, 425, and 426, respectively; SEQ ID NO: 429, 430, 431, 432, 433, and 434, respectively; SEQ ID NO: 437, 438, 439, 440, 441, and 442, respectively; SEQ ID NO: 445, 446, 447, 448, 449, and 450, respectively; SEQ ID NO: 453, 454, 455, 456, 457, and 458, respectively; SEQ ID NO: 461, 462, 463, 464, 465, and 466, respectively; SEQ ID NO: 469, 470, 471, 472, 473, and 474, respectively; SEQ ID NO: 477, 478, 479, 480, 481, and 482, respectively; SEQ ID NO: 485, 486, 487, 488, 489, and 490, respectively; SEQ ID NO: 495, 496, 497, 498, 499, and 500, respectively; SEQ ID NO: 503, 504, 505, 506, 507, and 508, respectively; SEQ ID NO: 511, 512, 513, 514, 515, and 516, respectively; SEQ ID NO: 519, 520, 521, 522, 523, and 524, respectively; SEQ ID NO: 527, 528, 529, 530, 531, and 532, respectively; SEQ ID NO: 535, 536, 537, 538, 539, and 540, respectively; SEQ ID NO: 543, 544, 545, 546, 547, and 548, respectively; SEQ ID NO: 551, 552, 553, 554, 555, and 556, respectively; SEQ ID NO: 559, 560, 561, 562, 563, and 564, respectively; SEQ ID NO: 567, 568, 569, 570, 571, and 572, respectively; SEQ ID NO: 575, 576, 577, 578, 579, and 580, respectively; SEQ ID NO: 583, 584, 585, 586, 587, and 588, respectively; SEQ ID NO: 591, 592, 593, 594, 595, and 596, respectively; SEQ ID NO: 599, 600, 601, 602, 603, and 604, respectively; SEQ ID NO: 607, 608, 609, 610, 611, and 612, respectively; SEQ ID NO: 615, 616, 617, 618, 619, and 620, respectively; SEQ ID NO: 623, 624, 625, 626, 627, and 628, respectively; SEQ ID NO: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NO: 639, 640, 641, 642, 643, and 644, respectively; SEQ ID NO: 647, 648, 649, 650, 651, and 652, respectively; SEQ ID NO: 655, 656, 657, 658, 659, and 660, respectively; SEQ ID NO: 663, 664, 665, 666, 667, and 668, respectively; SEQ ID NO: 671, 672, 673, 674, 675, and 676, respectively; SEQ ID NO: 679, 680, 681, 682, 683, and 684, respectively; SEQ ID NO: 687, 688, 689, 690, 691, and 692, respectively; SEQ ID NO: 695, 696, 697, 698, 699, and 700, respectively; SEQ ID NO: 705, 706, 707, 708, 709, and 710, respectively; SEQ ID NO: 725, 726, 727, 728, 729, and 730, respectively; SEQ ID NO: 733, 734, 735, 736, 737, and 738, respectively; SEQ ID NO: 741, 742, 743, 744, 745, and 746, respectively; SEQ ID NO: 749, 750, 751, 752, 753, and 754, respectively; SEQ ID NO: 759, 760, 761, 762, 763, and 764, respectively; SEQ ID NO: 767, 768, 769, 770, 771, and 772, respectively; SEQ ID NO: 775, 776, 777, 778, 779, and 780, respectively; SEQ ID NO: 783, 784, 785, 786, 787, and 788, respectively; SEQ ID NO: 791, 792, 793, 794, 795, and 796, respectively; SEQ ID NO: 799, 800, 801, 802, 803, and 804, respectively; SEQ ID NO: 807, 808, 809, 810, 811, and 812, respectively; SEQ ID NO: 815, 816, 817, 818, 819, and 820, respectively; SEQ ID NO: 823, 824, 825, 826, 827, and 828, respectively; SEQ ID NO: 831, 832, 833, 834, 835, and 836, respectively; SEQ ID NO: 839, 840, 841, 842, 843, and 844, respectively; SEQ ID NO: 847, 848, 849, 850, 851, and 852, respectively; SEQ ID NO: 855, 856, 857, 858, 859, and 860, respectively; SEQ ID NO: 863, 864, 865, 866, 867, and 868, respectively; SEQ ID NO: 871, 872, 873, 874, 875, and 876, respectively; SEQ ID NO: 879, 880, 881, 882, 883, and 884, respectively; SEQ ID NO: 887, 888, 889, 890, 891, and 892, respectively; SEQ ID NO: 895, 896, 897, 898, 899, and 900, respectively; SEQ ID NO: 903, 904, 905, 906, 907, and 908, respectively; SEQ ID NO: 911, 912, 913, 914, 915, and 916, respectively; SEQ ID NO: 919, 920, 921, 922, 923, and 924, respectively; SEQ ID NO: 927, 928, 929, 930, 931, and 932, respectively; SEQ ID NO: 935, 936, 937, 938, 939, and 940, respectively; SEQ ID NO: 945, 946, 947, 948, 949, and 950, respectively; SEQ ID NO: 953, 954, 955, 956, 957, and 958, respectively; SEQ ID NO: 961, 962, 963, 964, 965, and 966, respectively; SEQ ID NO: 969, 970, 971, 972, 973, and 974, respectively; SEQ ID NO: 977, 978, 979, 980, 981, and 982, respectively; SEQ ID NO: 985, 986, 987, 988, 989, and 990, respectively; SEQ ID NO: 997, 998, 999, 1000, 1001, and 1002, respectively; SEQ ID NO: 1005, 1006, 1007, 1008, 1009, and 1010, respectively; SEQ ID NO: 1013, 1014, 1015, 1016, 1017, and 1018, respectively; SEQ ID NO: 1021, 1022, 1023, 1024, 1025, and 1026, respectively; SEQ ID NO: 1029, 1030, 1031, 1032, 1033, and 1034, respectively; or SEQ ID NO: 1037, 1038, 1039, 1040, 1041, and 1042, respectively. [0547] In some cases, the L moiety of compound 3.1 comprises an antibody that targets an immune checkpoint selected from the group consisting of PDL1, B7H4, B7H3, and TIGIT. For example, in some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising at least 80% sequence identity to: SEQ ID NO: 13, 14, 15, 16, 17, and 18, respectively; SEQ ID NO: 77, 78, 79, 80, 81, and 82, , respectively; SEQ ID NO: 91, 92, 93, 94, 95, and 96, respectively; SEQ ID NO: 99, 100, 101, 102, 103, and 104, respectively; SEQ ID NO: 107, 108, 109, 110, 111, and 112, respectively; SEQ ID NO: 115, 116, 117, 118, 119, and 120, respectively; SEQ ID NO: 123, 124, 125, 126, 127, and 128, respectively; SEQ ID NO: 131, 132, 133, 134, 135, and 136, respectively; SEQ ID NO: 139, 140, 141, 142, 143, and 144, respectively; SEQ ID NO: 147, 148, 149, 150, 151, and 152, respectively; SEQ ID NO: 155, 156, 157, 158, 159, and 160, respectively; SEQ ID NO: 163, 164, 165, 166, 167, and 168, respectively; SEQ ID NO: 171, 172, 173, 174, 175, and 176, respectively; SEQ ID NO: 179, 180, 181, 182, 183, and 184, respectively; SEQ ID NO: 187, 188, 189, 190, 191, and 192, respectively; SEQ ID NO: 195, 196, 197, 198, 199, and 200, respectively; SEQ ID NO: 203, 204, 205, 206, 207 and 208, respectively; SEQ ID NO: 211, 212, 213, 214, 215, and 216, respectively; SEQ ID NO: 219, 220, 221, 222, 223, and 224, respectively; SEQ ID NO: 227, 228, 229, 230, 231, and 232, respectively; SEQ ID NO: 235, 236, 237, 238, 239, and 240, respectively; SEQ ID NO: 243, 244, 245, 246, 247, and 248, respectively; SEQ ID NO: 623, 624, 625, 626, 627, and 628, respectively; SEQ ID NO: 631, 632, 633, 634, 635, and 636, respectively; SEQ ID NO: 639, 640, 641, 642, 643, and 644, respectively; SEQ ID NO: 647, 648, 649, 650, 651, and 652, respectively; SEQ ID NO: 655, 656, 657, 658, 659, and 660, respectively; SEQ ID NO: 663, 664, 665, 666, 667, and 668, respectively; SEQ ID NO: 671, 672, 673, 674, 675, and 676, respectively; SEQ ID NO: 679, 680, 681, 682, 683, and 684, respectively; SEQ ID NO: 687, 688, 689, 690, 691, and 692, respectively; SEQ ID NO: 695, 696, 697, 698, 699, and 700, respectively; SEQ ID NO: 705, 706, 707, 708, 709, and 710, respectively; or SEQ ID NO: 1021, 1022, 1023, 1024, 1025, and 1026, respectively. [0548] In some embodiments, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprise at least 85% sequence identity to the respective 6 indicated sequences. In some cases, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprise at least 90% sequence identity to the respective 6 indicated sequences. In some cases, the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprise at least 95% sequence identity to the respective 6 indicated sequences. In some cases, the CDR- H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprise at most one mutation relative to the respective 6 indicated sequences. (viii) Exemplary Antibodies [0549] In some cases, the L moiety of compound 3.1 comprises an antibody that binds to PDL1. PDL1 is expressed in a broad range of cancers, as well as certain immune cells, and often serves as a primary mechanism for immune suppression in tumor microenvironments. The PDL1 agonism of PD-1 can act as an immune checkpoint, diminishing lymphocyte tumor infiltration, and T-cell receptor mediated proliferation and signaling. While PDL1 antagonism can reverse immune suppression, PDL1 targeting can also localize treatments to the sites of cancers, allowing drugs to selectively target cancer cells or stimulate immune responses in the presence of tumors. [0550] In some embodiments, the compound 3.1 comprises an anti-PDL1 antibody comprising CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, at least 98%, or at least 99% sequence identity to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18 respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, and 18, respectively. In some embodiments, a Ligand-Drug Conjugate corresponding to compound 3.1 in Table 3 is provided wherein L comprises any of the anti-PDL1 antibodies described above or L comprises an amino acid sequence with at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, at least 98%, or at least 99% sequence identity an amino acid sequences of SEQ ID NOs: 13, 14, 15, 16, 17, or 18. [0551] In some embodiments, the L moiety of compound 3.1 comprises an antibody comprising a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 1-4 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 2 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 3 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 4 and a light chain comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 5. [0552] In some embodiments, the L moiety of compound 3.1 comprises an antibody comprising a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 6-9 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 6 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 7 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 8 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10. In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NO: 9 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 10. [0553] In some embodiments, the L moiety of compound 3.1 comprises an antibody comprising a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 19 and a light chain variable region comprising an amino acid sequence that is at least 95% at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 20. [0554] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to EphA2. In some embodiments, the antibody comprises CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequences of SEQ ID NOs: 21, 22, 23, 24, 25, and 26, respectively. [0555] In some embodiments, the anti-EphA2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, the anti-EphA2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 29 or SEQ ID NO: 30 and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of the amino acid sequence of SEQ ID NO: 31. In some embodiments, the anti-EphA2 antibody comprises a heavy chain comprising the amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 32 or SEQ ID NO: 33 and a light chain comprising the amino acid sequence of SEQ ID NO: 34. In some embodiments, the anti-EphA2 antibody comprises a heavy chain that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NO: 35 or SEQ ID NO: 36 and a light chain comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the antibody is h1C1 or 1C1. [0556] In some embodiments, the anti-EphA2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 28. [0557] In some embodiments, the L moiety of compond 3.1 comprises an antibody that binds to CD30. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 38, 39, 40, 41, 42, and 43, respectively. In some embodiments, the anti-CD30 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 46 or 47 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 48. In some embodiments, the anti- CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 44 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 45. [0558] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD228. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 49, 50, 51, 52, 53, and 54, respectively. In some embodiments, the anti-CD228 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 55 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the anti-CD228 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either of SEQ ID NO: 57 or 58 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-CD228 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either of SEQ ID NO: 60 or 61 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 62. [0559] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to avB6. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 63, 64, 65, 66, 67, and 68, respectively. In some embodiments, the anti-H2A2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70. In some embodiments, the anti-H2A2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 71 or 72 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the anti- H2A2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 74 or 75 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76. In some embodiments, the anti-avB6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70. In some embodiments, the anti-avB6 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 71 or 72 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73. In some embodiments, the anti- avB6 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of either SEQ ID NO: 74 or 75 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76. [0560] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to B7H4. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 77-82, SEQ ID NOs: 91-96, SEQ ID NOs: 99-104, SEQ ID NOs: 107-112, SEQ ID NOs: 115-120, SEQ ID NOs: 123-128, SEQ ID NOs: 131-136, SEQ ID NOs: 139-144, SEQ ID NOs: 147-152, SEQ ID NOs: 155-160, SEQ ID NOs: 163-168, SEQ ID NOs: 171-176, SEQ ID NOs: 179- 184, SEQ ID NOs: 187-192, SEQ ID NOs: 195-200, SEQ ID NOs: 203-208, SEQ ID NOs: 211-216, SEQ ID NOs: 219-224, SEQ ID NOs: 227-232, SEQ ID NOs: 235-240, and SEQ ID NOs: 243-248. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively) each comprising at most one mutation relative to an amino acid sequence from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 77-82, SEQ ID NOs: 91-96, SEQ ID NOs: 99- 104, SEQ ID NOs: 107-112, SEQ ID NOs: 115-120, SEQ ID NOs: 123-128, SEQ ID NOs: 131-136, SEQ ID NOs: 139-144, SEQ ID NOs: 147-152, SEQ ID NOs: 155-160, SEQ ID NOs: 163-168, SEQ ID NOs: 171-176, SEQ ID NOs: 179-184, SEQ ID NOs: 187-192, SEQ ID NOs: 195-200, SEQ ID NOs: 203-208, SEQ ID NOs: 211-216, SEQ ID NOs: 219-224, SEQ ID NOs: 227-232, SEQ ID NOs: 235-240, and SEQ ID NOs: 243-248. In some cases, the anti-B7H4 antibody comprises a heavy chain and a light chain comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 85 and 87, SEQ ID NO: 86 and 87, SEQ ID NO: 88 and 90, SEQ ID NO: 89 and 90, SEQ ID NO: 251 and 252, , SEQ ID NO: 253 and 254, SEQ ID NO: 255 and 256, SEQ ID NO: 257 and 258, SEQ ID NO: 259 and 260, SEQ ID NO: 261 and 262, SEQ ID NO: 263 and 264, SEQ ID NO: 265 and 266, SEQ ID NO: 267 and 268, SEQ ID NO: 269 and 270, SEQ ID NO: 271 and 272, SEQ ID NO: 273 and 274, SEQ ID NO: 275 and 276, SEQ ID NO: 277 and 278, SEQ ID NO: 279 and 280, SEQ ID NO: 281 and 282, SEQ ID NO: 283 and 284, SEQ ID NO: 285 and 286, SEQ ID NO: 287 and 288, or SEQ ID NO: 289 and 290, respectively. In some embodiments, the anti-B7H4 antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 83 and 84, SEQ ID NO: 97 and 98, SEQ ID NO: 105 and 106, SEQ ID NO: 113 and 114, SEQ ID NO: 121 and 122, SEQ ID NO: 129 and 130, SEQ ID NO: 137 and 138, SEQ ID NO: 153 and 154, SEQ ID NO: 161 and 162, SEQ ID NO: 169 and 170, SEQ ID NO: 177 and 178, SEQ ID NO: 185 and 186, SEQ ID NO: 193 and 194, SEQ ID NO: 201 and 202, SEQ ID NO: 209 and 210, SEQ ID NO: 217 and 218, SEQ ID NO: 225 and 226, SEQ ID NO: 233 and 234, SEQ ID NO: 241 and 242, or SEQ ID NO: 249 and 250, respectively. [0561] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD70. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 291, 292, 293, 294, 295, and 296, respectively. In some embodiments, the anti-CD70 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 297 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 298. In some embodiments, the anti-CD70 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 299 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 300. [0562] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to TROP2. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 301, 302, 303, 304, 305, and 306, respectively. In some cases, an antibody provided herein binds to TROP2. In some such cases, the antibody comprises CDR- H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 309, 310, 311, 312, 313, and 314 respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 309, 310, 311, 312, 313, and 314, respectively. In some embodiments, the anti-TROP2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 307 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 308. In some embodiments, the anti-TROP2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 315 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 316. [0563] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to MICA. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 317, 318, 319, 320, 321, and 322, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 325, 326, 327, 328, 329, and 330, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 333, 334, 335, 336, 337, and 338, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 341, 342, 343, 344, 345, and 346, respectively. In some embodiments, the anti- MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 323 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 324. In some embodiments, the anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 331 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 332. In some embodiments, the anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 340 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 340. In some embodiments, the anti-MICA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 347 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 348. [0564] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD51. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 349, 350, 351, 352, 353, and 354, respectively. In some cases, an antibody provided herein binds to CD51. In some such cases, the antibody comprises CDR- H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 357, 358, 359, 360, 361, and 362, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 357, 358, 359, 360, 361, and 362, respectively. In some embodiments, the anti-CD51 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 355 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 356. In some embodiments, the anti-CD51 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 363 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 364. [0565] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to gpA33. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 365, 366, 367, 368, 369, and 370, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 365, 366, 367, 368, 369, and 370, respectively. In some embodiments, the anti-gpA33 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 371 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 372. [0566] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to IL1Rap. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 373, 374, 375, 376, 377, and 378, respectively. In some embodiments, the anti-IL1Rap antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 379 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 380. [0567] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to EpCAM. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 381-386, SEQ ID NOs: 389-394, SEQ ID NOs: 397-402, SEQ ID NOs: 405-410, SEQ ID NOs: 413- 418, or SEQ ID NOs: 421-426. In some embodiments, the anti-EpCAM antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 387 and 388, SEQ ID NO: 395 and 396, SEQ ID NO: 403 and 404, SEQ ID NO: 411 and 412, SEQ ID NO: 419 and 420, or SEQ ID NO: 427 and 428, respectively. [0568] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD352. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 429, 430, 431, 432, 433, and 434, respectively. In some embodiments, the anti-CD352 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 435 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 436. [0569] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CS1. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 437, 438, 439, 440, 441, and 442, respectively. In some embodiments, the anti-CS1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 443 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 444. [0570] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD38. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 445, 446, 447, 448, 449, and 450, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 445, 446, 447, 448, 449, and 450, respectively. In some embodiments, the anti-CD38 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 451 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 452. [0571] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD25. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 453, 454, 455, 456, 457, and 458, respectively. In some embodiments, the anti-CD25 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 459 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 460. [0572] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to ADAM9. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 461, 462, 463, 464, 465, and 466, respectively. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR- L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 469, 470, 471, 472, 473, and 474, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 469, 470, 471, 472, 473, and 474, respectively. In some embodiments, the anti-ADAM9 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 467 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 468. In some embodiments, the anti- ADAM9 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 475 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 476. [0573] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD59. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 477, 478, 479, 480, 481, and 482, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 477, 478, 479, 480, 481, and 482, respectively. In some embodiments, the anti-CD59 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 483 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 484. [0574] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD19. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 485, 486, 487, 488, 489, and 490, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 485, 486, 487, 488, 489, and 490, respectively. In some embodiments, the anti-CD19 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 491 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 492. In some embodiments, the anti-CD19 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 493 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 494. [0575] In some embodiments, the L moiety of compond 3.1 comprises an antibody that binds to CD138. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 495, 496, 497, 498, 499, and 500, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 495, 496, 497, 498, 499, and 500, respectively. In some embodiments, the anti-CD138 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 501 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 502. [0576] In some embodiments, the L moiety of compond 3.1 comprises an antibody that binds to CD166. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 503, 504, 505, 506, 507, and 508, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 503, 504, 505, 506, 507, and 508, respectively. In some embodiments, the anti-CD166 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 509 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 510. [0577] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD56. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 511, 512, 513, 514, 515, and 516, respectively. In some embodiments, the anti-CD56 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 517 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 518. [0578] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD74. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 519, 520, 521, 522, 523, and 524, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 519, 520, 521, 522, 523, and 524, respectively. In some embodiments, the anti-CD74 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 525 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 526. [0579] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CEACAM5. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 527, 528, 529, 530, 531, and 532, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 527, 528, 529, 530, 531, and 532, respectively. In some embodiments, the anti-CEACAM5 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 533 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 534. [0580] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CanAg. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 535, 536, 537, 538, 539, and 540, respectively. In some embodiments, the anti-CanAg antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 541 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 542. [0581] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to DLL-3. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 543, 544, 545, 546, 547, and 548, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 543, 544, 545, 546, 547, and 548, respectively. In some embodiments, the anti-DLL-3 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 549 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 550. [0582] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to DPEP-3. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 551, 552, 553, 554, 555, and 556, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 551, 552, 553, 554, 555, and 556, respectively. In some embodiments, the anti-DPEP-3 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 557 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 558. [0583] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to EGFR. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 559-564, SEQ ID NOs: 567-572, SEQ ID NOs: 575-580, and SEQ ID NOs: 895-900. In some embodiments, the anti-EGFR antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 565 and 566, SEQ ID NO: 573 and 574, SEQ ID NO: 581 and 582, or SEQ ID NO: 901 and 902, respectively. [0584] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to FRa. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 583, 584, 585, 586, 587, and 588, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 583, 584, 585, 586, 587, and 588, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 591, 592, 593, 594, 595, and 596, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 591, 592, 593, 594, 595, and 596, respectively. In some embodiments, the anti-FRa antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 589 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 590. In some embodiments, the anti-FRa antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 597 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 598. [0585] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to MUC-1. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 599, 600, 601, 602, 603, and 604, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 599, 600, 601, 602, 603, and 604, respectively. In some embodiments, the anti-MUC-1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 605 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 606. [0586] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to Mesothelin. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR- H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 607, 608, 609, 610, 611, and 612, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 607, 608, 609, 610, 611, and 612, respectively. In some embodiments, the anti-Mesothelin antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 613 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 614. [0587] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to ROR-1. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 615, 616, 617, 618, 619, and 620, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 615, 616, 617, 618, 619, and 620, respectively. In some embodiments, the anti-ROR-1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 621 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 622. [0588] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to B7H3. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, respectively) of which each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95%, or 100% sequence identity to amino acid sequences from a set of amino acid sequences selected from the group consisting of SEQ ID NOs: 623-628, SEQ ID NOs: 631-636, SEQ ID NOs: 639-644, SEQ ID NOs: 647-652, SEQ ID NOs: 655- 660, SEQ ID NOs: 663-668, SEQ ID NOs: 671-676, SEQ ID NOs: 679-684, SEQ ID NOs: 687-692, SEQ ID NOs: 695-700, and SEQ ID NOs: 705-710. In some embodiments, the anti- B7H3 antibody comprises a heavy chain variable region and a light chain variable region comprising amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or at least 100% identical to the amino acid sequences of SEQ ID NO: 629 and 630, SEQ ID NOs: 637 and 638, SEQ ID NOs: 645 and 646, SEQ ID NOs: 653 and 654, SEQ ID NOs: 661 and 662, SEQ ID NOs: 669 and 670, SEQ ID NOs: 677 and 678, SEQ ID NOs: 685 and 686, SEQ ID NOs: 693 and 694, SEQ ID NOs: 701 and 702, SEQ ID NOs: 703 and 704, SEQ ID NOs: 711 and 712, SEQ ID NOs: 713 and 714, and SEQ ID NOs: 715 and 716, respectively. [0589] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to HER3. In some embodiments, the anti-HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 717 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 718. In some cases, an antibody provided herein binds to HER3. In some embodiments, the anti- HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 719 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 720. In some cases, an antibody provided herein binds to HER3. In some embodiments, the anti-HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 721 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 722. In some cases, an antibody provided herein binds to HER3. In some embodiments, the anti- HER3 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 723 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 724. [0590] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to PTK7. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 725, 726, 727, 728, 729, and 730, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 725, 726, 727, 728, 729, and 730, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 733, 734, 735, 736, 737, and 738, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 733, 734, 735, 736, 737, and 738, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 741, 742, 743, 744, 745, and 746, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 741, 742, 743, 744, 745, and 746, respectively. In some cases, the anti-PTK7 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 731 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 732. In some cases, the anti-PTK7 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 739 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 740. In some cases, the anti-PTK7 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 747 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 748. [0591] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to ZIP6. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 749, 750, 751, 752, 753, and 754, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 749, 750, 751, 752, 753, and 754, respectively. In some cases, the anti-ZIP6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 755 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 756. In some embodiments, the anti-ZIP6 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 757 and a light chain comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 758. [0592] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to Integrin αvβ6. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 759, 760, 761, 762, 763, and 764, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 759, 760, 761, 762, 763, and 764, respectively. In some embodiments, the anti- Integrin αvβ6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 765 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 766. [0593] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD48. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 767, 768, 769, 770, 771, and 772, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 767, 768, 769, 770, 771, and 772, respectively. In some embodiments, the anti-CD48 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 773 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 774. [0594] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to IGF-1R. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 775, 776, 777, 778, 779, and 780, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 775, 776, 777, 778, 779, and 780, respectively. In some embodiments, the anti-IGF-1R antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 781 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 782. [0595] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to Claudin-18.2. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 783, 784, 785, 786, 787, and 788, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 783, 784, 785, 786, 787, and 788, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 791, 792, 793, 794, 795, and 796, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 791, 792, 793, 794, 795, and 796, respectively. In some embodiments, the anti-Claudin-18.2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 789 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 790. In some embodiments, the anti-Claudin-18.2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 797 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 798. [0596] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to Nectin-4. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 799, 800, 801, 802, 803, and 804, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 799, 800, 801, 802, 803, and 804, respectively. In some embodiments, the anti-Nectin-4 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 805 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 806. [0597] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to SLTRK6. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 807, 808, 809, 810, 811, and 812, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 807, 808, 809, 810, 811, and 812, respectively. In some embodiments, the anti-SLTRK6 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 813 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 814. [0598] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD142. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 815, 816, 817, 818, 819, and 820, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 815, 816, 817, 818, 819, and 820, respectively. In some embodiments, the anti-CD142 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 821 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 822. [0599] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to Sialyl-Thomsen-nouveau antigen (STn). In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 823, 824, 825, 826, 827, and 828, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 823, 824, 825, 826, 827, and 828, respectively. [0600] In some embodiments, the anti-STn antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 829 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 830. [0601] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD20. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 831, 832, 833, 834, 835, and 836, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 831, 832, 833, 834, 835, and 836, respectively. In some embodiments, the anti-CD20 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 837 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 838. [0602] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to HER2. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 839, 840, 841, 842, 843, and 844, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 839, 840, 841, 842, 843, and 844, respectively. In some embodiments, the anti-HER2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 845 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 846. [0603] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD79b. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 847, 848, 849, 850, 851, and 852, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 847, 848, 849, 850, 851, and 852, respectively. In some embodiments, the anti-CD79b antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 853 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 854. [0604] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to NaPi2B. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 855, 856, 857, 858, 859, and 860, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 855, 856, 857, 858, 859, and 860, respectively. In some embodiments, the anti-NaPi2B antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 861 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 862. [0605] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to Muc16. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 863, 864, 865, 866, 867, and 868, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 863, 864, 865, 866, 867, and 868, respectively. In some embodiments, the anti-Muc16 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 869 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 870. [0606] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to STEAP1. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 871, 872, 873, 874, 875, and 876, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 871, 872, 873, 874, 875, and 876, respectively. In some embodiments, the anti-STEAP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 877 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 878. [0607] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to BCMA. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 879, 880, 881, 882, 883, and 884, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 879, 880, 881, 882, 883, and 884, respectively. In some embodiments, the anti-BCMA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 885 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 886. [0608] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to c-Met. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 887, 888, 889, 890, 891, and 892, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 887, 888, 889, 890, 891, and 892, respectively. In some embodiments, the anti-c-Met antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 893 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 893. [0609] In some embodiments, the L moiety of compound comprises an antibody that binds to SLAMF7. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 903, 904, 905, 906, 907, and 908, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 903, 904, 905, 906, 907, and 908, respectively. In some embodiments, the anti-SLAMF7 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 909 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 910. [0610] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to C4.4a. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 911, 912, 913, 914, 915, and 916, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 911, 912, 913, 914, 915, and 916, respectively. In some embodiments, the anti-C4.4a antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 917 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 918. [0611] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to GCC. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 919, 920, 921, 922, 923, and 924, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 919, 920, 921, 922, 923, and 924, respectively. In some embodiments, the anti-GCC antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 925 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 926. [0612] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to Axl. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 927, 928, 929, 930, 931, and 932, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 927, 928, 929, 930, 931, and 932, respectively. In some embodiments, the anti-Axl antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 933 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 933. [0613] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to transmembrane glycoprotein NMB (gpNMB). In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 935, 936, 937, 938, 939, and 940, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 935, 936, 937, 938, 939, and 940, respectively. In some embodiments, the anti-gpNMB antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 941 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 942. In some embodiments, the anti-gpNMB antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 943 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 944. [0614] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to Prolactin receptor. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 945, 946, 947, 948, 949, and 950, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 945, 946, 947, 948, 949, and 950, respectively. In some embodiments, the anti-Prolactin receptor antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 951 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 952. [0615] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to FGFR2. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 953, 954, 955, 956, 957, and 958, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 953, 954, 955, 956, 957, and 958, respectively. In some embodiments, the anti-FGFR2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 959 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 960. [0616] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CDCP1. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR- L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 961, 962, 963, 964, 965, and 966, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 969, 970, 971, 972, 973, and 974, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 961, 962, 963, 964, 965, and 966, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 969, 970, 971, 972, 973, and 974, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 977, 978, 979, 980, 981, and 982, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 977, 978, 979, 980, 981, and 982, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 985, 986, 987, 988, 989, and 990, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 985, 986, 987, 988, 989, and 990, respectively. In some embodiments, the anti- CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 967 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 968. In some embodiments, the anti-CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 975 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 976. In some embodiments, the anti-CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 983 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 984. In some embodiments, the anti-CDCP1 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 991 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 992. [0617] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to ASCT2. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 997, 998, 999, 1000, 1001, and 1002, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 997, 998, 999, 1000, 1001, and 1002, respectively. In some embodiments, the anti-ASCT2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 993 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 994. In some embodiments, the anti-ASCT2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 995 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 996. In some embodiments, the anti-ASCT2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1003 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1004. [0618] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD123. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1005, 1006, 1007, 1008, 1009, and 1010, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1005, 1006, 1007, 1008, 1009, and 1010, respectively. In some embodiments, the anti-CD123 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1011 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1012. [0619] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to GPC3. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1013, 1014, 1015, 1016, 1017, and 1018 respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1013, 1014, 1015, 1016, 1017, and 1018, respectively. In some embodiments, the anti-TIGIT antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1027 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1028. [0620] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to TIGIT. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1021, 1022, 1023, 1024, 1025, and 1026, respectively. In some embodiments, the anti-BCMA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1043 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1044. [0621] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to CD33. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1029, 1030, 1031, 1032, 1033, and 1034, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1029, 1030, 1031, 1032, 1033, and 1034, respectively. In some embodiments, the anti-CD33 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1035 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1036. [0622] In some embodiments, the L moiety of compound 3.1 comprises an antibody that binds to BCMA. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences comprising at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 1037, 1038, 1039, 1040, 1041, and 1042, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences each comprising at most one mutation relative to the amino acid sequences of SEQ ID NOs: 1037, 1038, 1039, 1040, 1041, and 1042, respectively. In some embodiments, the anti-BCMA antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1043 and a light chain variable region comprising an amino acid sequence that is at least 80% at least 85%, at least 90%, at least 95%, at least 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 1044. [0623] Throughout this application, unless the context indicates otherwise, references to a compound of Formula (I), (I'), (I*), (II), or any subformula thereof, includes all subgroups of Formula (I), (I'), (I*), (II), or any subformula thereof, defined herein, including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and/or described herein. References to a compound of Formula (I), (I'), (I*), (II), or any subformula thereof, include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and/or protected forms thereof. In some embodiments, references to a compound of Formula (I), (I'), (I*), (II), or any subformula thereof, include polymorphs, solvates, co-crystals, isomers, tautomers and/or oxides thereof. In some embodiments, references to a compound of Formula (I), (I'), (I*), (II), or any subformula thereof, include polymorphs, solvates, and/or co-crystals thereof. In some embodiments, references to a compound of Formula (I), (I'), (I*), (II), or any subformula thereof, include isomers, tautomers and/or oxides thereof. In some embodiments, references to a compound of Formula (I), (I'), (I*), (II), or any subformula thereof, include solvates thereof. Similarly, the term “salts” includes solvates of salts of compounds. [0624] Any formula given herein, such as Formula (I), (I'), (I*), (II), or any subformula thereof, is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. Where a compound of one of Tables 1, 2, or 3 is depicted with a particular stereochemical configuration, also provided herein is any alternative stereochemical configuration of the compound, as well as a mixture of stereoisomers of the compound in any ratio. For example, where a compound of Tables 1, 2, or 3 has a stereocenter that is in an “S” stereochemical configuration, also provided herein is enantiomer of the compound wherein that stereocenter is in an “R” stereochemical configuration. Likewise, when a compound of Tables 1, 2, or 3 has a stereocenter that is in an “R” configuration, also provided herein is enantiomer of the compound in an “S” stereochemical configuration. Also provided are mixtures of the compound with both the “S” and the “R” stereochemical configuration. Additionally, if a compound of Tables 1, 2, or 3 has two or more stereocenters, also provided are any enantiomer or diastereomer of the compound. For example, if a compound of Tables 1, 2, or 3 contains a first stereocenter and a second stereocenter with “R” and “R” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “S” and “S” stereochemical configurations, respectively, “S” and “R” stereochemical configurations, respectively, and “R” and “S” stereochemical configurations, respectively. If a compound of Tables 1, 2, or 3 contains a first stereocenter and a second stereocenter with “S” and “S” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “R” and “R” stereochemical configurations, respectively, “S” and “R” stereochemical configurations, respectively, and “R” and “S” stereochemical configurations, respectively. If a compound of Tables 1, 2, or 3 contains a first stereocenter and a second stereocenter with “S” and “R” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “R” and “S” stereochemical configurations, respectively, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively. Similarly, if a compound of Tables 1, 2, or 3 contains a first stereocenter and a second stereocenter with “R” and “S” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “S” and “R” stereochemical configurations, respectively, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to refer also to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly. In some embodiments, the solvent is water and the solvates are hydrates. [0625] The compounds depicted herein may be present as salts even if salts are not depicted, and it is understood that the compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts. [0626] Embodiments are contemplated wherein any variation or embodiment of Q, D, Z or Z', A, B, S*, RL, Y, W, L, Za, Xb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Ra, Rb, E, X, subscript n, subscript n, subscript q, and/or subscript p provided herein is combined with every other variation or embodiment of Q, D, Z or Z', A, B, S*, RL, Y, W, L, Za, Xb, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Ra, Rb, E, X, subscript n, subscript n, subscript q, and/or subscript p, as if each combination had been individually and specifically described. [0627] In some embodiments, any of the compounds described herein, such as a compound of Formula (I), (I'), (I*), (II), or any subformula thereof, or a compound of any one of Tables 1, 2 or 3, or a salt of any of the foregoing, may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds are sometimes prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds. In some aspects, hydrogen atoms are be replaced with deuterium atoms using other methods known in the art. [0628] Other embodiments will be apparent to those skilled in the art from the following detailed description. [0629] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. Other exemplary ligand-drug conjugates [0630] gpNMB is a type 1 transmembrane protein that has been shown to be pro- metastatic, and high expression is correlated with worse cancer patient survival. Taya et al., Steroids, 2017, 133:102. It is expressed in many cancer indications, including melanoma, squamous non-small-cell lung cancer (sqNSCLC), Head and Neck, and esophageal cancers. An antibody-drug conjugate, glembatumumab vedotin, was in melanoma and breast cancer clinical trials, but activity was limited by off target toxicities at the MTD (Ott et al., Cancer, 2019, 125:1113). Therefore, the present inventors conceived that a gpNMB-targeted antibody-drug conjugate would pair well with a payload with an improved therapeutic index. [0631] Thus, provided herein are ligand-drug conjugates, such as of compound 3.1, wherein the L moiety is an anti-gpNMB antibody, or antigen-binding fragment thereof. [0632] The antibody, or antigen-binding fragment thereof, in some embodiments bind to gpNMB with an affinity (e.g., EC50) of less than 10 nM, 5 nM, 2 nM, 1 nM, 500 pM, 250 pM, 100 pM, 50 pM, 25 pM, 10 pM, or 1 pM. In some embodiments, the antibody, or antigen-binding fragment thereof, binds to gpNMB with an affinity of between 5-10 nM, 1-5 nM, 500 pM – 1 nM, 100 – 250 pM, 50 – 100 pM, 10-50 pM, or 1-10 pM. [0633] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises the CDRs, the varianble domains, and/or the heavy and light chain amino acid sequences as indicated in Table D1 and D2, below. Table D1. Exemplary anti-gpNMB antibody CDR sequences.
Figure imgf000274_0001
Table D2. Exemplary anti-gpNMB variable domain, light chain, and heavy chain sequences.
Figure imgf000274_0002
Figure imgf000275_0001
[0634] Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise the 6 CDRs as follows: a CDR-H1, a CDR-H2, a CDR-H3, a CDR-L1, a CDR-L2, and a CDR-L3 comprising the amino acid sequences of SEQ ID NOs:935-940, respectively. [0635] Some of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise a VH comprising the amino acid sequence of SEQ ID NO:941 and a VL comprising the amino acid sequence of SEQ ID NO:942. [0636] Some of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise a HC comprising the amino acid sequence of SEQ ID NO:943 and a LC comprising the amino acid sequence of SEQ ID NO:944. [0637] In other embodiments, the antibody, or antigen-binding fragment thereof, that are provided include or are derived from one or more of the CDRs, variable heavy chains, variable light chains, heavy chains, and/or light chains of the antibodies listed in Tables D1 and D2, or variants or derivatives thereof. [0638] Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise the 6 CDRs as follows: a CDR-H1, a CDR-H2, a CDR-H3 from the variable heavy chain sequence comprising the amino acid sequence of SEQ ID NO:941, and a CDR-L1, a CDR-L2, and a CDR-L3 from the variable light chain sequence comprising the amino acid sequence of SEQ ID NO:942, wherein the CDRs are defined by the IMGT CDR numbering scheme. [0639] Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise the 6 CDRs as follows: a CDR-H1, a CDR-H2, a CDR-H3 from the variable heavy chain sequence comprising the amino acid sequence of SEQ ID NO:941, and a CDR-L1, a CDR-L2, and a CDR-L3 from the variable light chain sequence comprising the amino acid sequence of SEQ ID NO:942, wherein the CDRs are defined by the Kabat CDR numbering scheme. [0640] Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise the 6 CDRs as follows: a CDR-H1, a CDR-H2, a CDR-H3 from the variable heavy chain sequence comprising the amino acid sequence of SEQ ID NO:941, and a CDR-L1, a CDR-L2, and a CDR-L3 from the variable light chain sequence comprising the amino acid sequence of SEQ ID NO:942, wherein the CDRs are defined by the AbM CDR numbering scheme. [0641] Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise the 6 CDRs as follows: a CDR-H1, a CDR-H2, a CDR-H3 from the variable heavy chain sequence comprising the amino acid sequence of SEQ ID NO:941, and a CDR-L1, a CDR-L2, and a CDR-L3 from the variable light chain sequence comprising the amino acid sequence of SEQ ID NO:942, wherein the CDRs are defined by the Chothia CDR numbering scheme. [0642] Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise the 6 CDRs as follows: a CDR-H1, a CDR-H2, a CDR-H3 from the variable heavy chain sequence comprising the amino acid sequence of SEQ ID NO:941, and a CDR-L1, a CDR-L2, and a CDR-L3 from the variable light chain sequence comprising the amino acid sequence of SEQ ID NO:942, wherein the CDRs are defined by the Contact CDR numbering scheme. [0643] Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise a VH comprising a CDR-H1, a CDR-H2, and a CDR-H3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDR-H1 reference sequence has the amino acid sequence of SEQ ID NO:935, the CDR-H2 reference sequence has the amino acid sequence of SEQ ID NO:936, and the CDR-H3 reference sequence has the amino acid sequence of SEQ ID NO:937. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0644] Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise a VL comprising a CDR-L1, a CDR-L2, and a CDR-L3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDR-L1 reference sequence has the amino acid sequence of SEQ ID NO:938, the CDR-L2 reference sequence has the amino acid sequence of SEQ ID NO:939, and the CDR-L3 reference sequence has the amino acid sequence of SEQ ID NO:940. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0645] Certain of the antibodies, or antigen-binding fragments thereof, disclosed herein comprise a VH comprising a CDR-H1, a CDR-H2, and a CDR-H3, wherein the CDRs of the VH collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDR-H1 reference sequence has the amino acid sequence of SEQ ID NO:935, the CDR-H2 reference sequence has the amino acid sequence of SEQ ID NO:936, and the CDR-H3 reference sequence has the amino acid sequence of SEQ ID NO:937; and a VL comprising a CDR-L1, a CDR-L2, and a CDR-L3, wherein the CDRs of the VL collectively have at most 1, 2, 3, 4, or 5 amino acid changes relative to a corresponding CDR reference sequence, and wherein the CDR-L1 reference sequence has the amino acid sequence of SEQ ID NO:938, the CDR-L2 reference sequence has the amino acid sequence of SEQ ID NO:939, and the CDR-L3 reference sequence has the amino acid sequence of SEQ ID NO:940. In such embodiments, the amino acid changes typically are insertions, deletions and/or substitutions. In some of these embodiments, the collective number of amino acid changes are 1-3; in other embodiments, the collective number of amino acid changes are 1 or 2. In certain of the foregoing embodiments, the changes are conservative amino acid substitutions. [0646] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a VH domain, wherein the VH domain sequence has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:941, provided the antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB. In certain embodiments, such an antibody, or antigen- binding fragment thereof, contains substitutions (e.g., conservative substitutions), insertions, and/or deletions relative to the reference sequence (i.e., SEQ ID NO:941), provided that such an antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB. In certain embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:941. In some embodiments, 1-5 or 1-3 amino acids have been substituted, inserted and/or deleted in the VH sequence. In certain of these embodiments, such substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the framework regions). [0647] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises a VL domain, wherein the VL domain sequence has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:942, provided the antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB. In certain embodiments, such an antibody, or antigen-binding fragment thereof, contains substitutions (e.g., conservative substitutions), insertions, and/or deletions relative to the reference sequence (i.e., SEQ ID NO:942), provided that such an antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB. In certain embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids have been substituted, inserted and/or deleted in SEQ ID NO:942. In some embodiments, 1-5 or 1-3 amino acids have been substituted, inserted and/or deleted in the VL sequence. In certain of these embodiments, such substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the framework regions). [0648] In some embodiments, the antibody, or antigen-binding fragment thereof, comprises: a VH domain, wherein the VH domain sequence has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:941, provided the antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB; and a VL domain, wherein the VL domain sequence has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:942, provided the antibody, or antigen- binding fragment thereof, retains the ability to bind to gpNMB. In certain embodiments, such an antibody, or antigen-binding fragment thereof, contains substitutions (e.g., conservative substitutions), insertions, and/or deletions relative to the reference sequence (i.e., SEQ ID NO:941 for the VH domain and SEQ ID NO:942 for the VL domain), provided that such an antibody, or antigen-binding fragment thereof, retains the ability to bind to gpNMB. In certain embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids have been substituted, inserted and/or deleted in the VH and/or the VL sequence. In some embodiments, 1-5 or 1-3 amino acids have been substituted, inserted and/or deleted in the VH and/or VL sequence. In other embodiments, 1-5 or 1-3 amino acids have been substituted, inserted and/or deleted in the VH and VL sequence collectively. In certain of these embodiments, such substitutions, insertions, or deletions occur in regions outside the CDRs (i.e., in the FRs). [0649] In a further embodiment, an antibody, or antigen-binding fragment thereof, comprises an HC comprising the amino acid sequence of SEQ ID NO:943, and a LC comprising the amino acid sequence of SEQ ID NO:944. [0650] The antibody, or antigen-binding fragment thereof, as described herein can be an antibody in any form. As such, the antibody, or antigen-binding fragment thereof, described in any of the above embodiments can be monoclonal, and may be multispecific, human, humanized or chimeric antibodies, single chain antibodies, Fab fragments, F(ab') fragments, fragments produced by a Fab expression library, and gpNMB-binding fragments of any of the above. The antibodies can be of any immunoglobulin isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. [0651] In certain embodiments, an antibody, or antigen-binding fragment thereof, with the CDRs and/or variable domain sequences described herein is an antigen-binding fragment (e.g., human antigen-binding fragments) including, but are not limited to, Fab, Fab' and F(ab')2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain. [0652] The antibody, or antigen-binding fragment thereof, can be monospecific or part of a bispecific or trispecific antibody, or antigen-binding fragments thereof, or part of an antibody, or antigen-binding fragment thereof, of greater multi-specificity. Multispecific antibodies can be specific for different epitopes of gpNMB or may be specific for both gpNMB and a heterologous protein. [0653] The antibodies, or antigen-binding fragments thereof, in any of the foregoing embodiments can be an antibody in any form. As such, the antibody, or antigen-binding fragment thereof, described in any of the above embodiments can be, for example, a monoclonal antibody, a multispecific antibody, a human, humanized or chimeric antibody, and gpNMB binding fragments of any of the above, such as a single chain antibody, an Fab fragment, an F(ab') fragment, or a fragment produced by a Fab expression library. The antibodies can be of any immunoglobulin isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) or subclass. [0654] In certain embodiments, a antibody, or antigen-binding fragment thereof, with the CDR and/or variable domain sequences described herein is an antigen-binding fragment (e.g., human antigen-binding fragments) and include, but are not limited to, Fab, Fab' and F(ab')2, Fd, single-chain Fvs (scFv), single-chain antibodies, disulfide-linked Fvs (sdFv) and fragments comprising either a VL or VH domain. Antigen-binding fragments, including single-chain antibodies, may comprise the variable region(s) alone or in combination with the entirety or a portion of the following: hinge region, CH1, CH2, CH3 and CL domains. Also included in the present disclosure are antigen-binding fragments comprising any combination of variable region(s) with a hinge region, CH1, CH2, CH3 and CL domains. [0655] The antibody, or antigen-binding fragment thereof, can be monospecific, bispecific, trispecific or of greater multi specificity. Multispecific antibodies can be specific for different epitopes of gpNMB or may be specific for both gpNMB as well as for a heterologous protein. See, e.g., PCT publications WO 93/17715; WO 92/08802; WO 91/00360; WO 92/05793; Tutt, et al., 1991, J. Immunol. 147:6069; U.S. Pat. Nos. 4,474,893; 4,714,681; 4,925,648; 5,573,920; 5,601,819; and Kostelny et al., 1992, J. Immunol. 148:1547 1553. [0656] In any of the embodiments described herein, one or several amino acids (e.g., 1, 2, 3 or 4) at the amino or carboxy terminus of the light and/or heavy chain, such as the C- terminal lysine of the heavy chain, may be missing or derivitized in some or all of the molecules in a composition. One specific example of such a modification, is an antibody, or antigen-binding fragment thereof, in which the carboxy terminal lysine of the heavy chain is missing (e.g., as part of a post-translational modification). Furthermore, it should be understood that any of the sequences described herein include post-translational modifications to the specified sequence during expression of the antibody, or antigen-binding fragment thereof, in cell culture (e.g., a CHO cell culture). [0657] In other embodiments, the moiety L of compound 3.1 is not an antibody or antigen-binding fragment thereof but instead comprises a non-antibody scaffold into which one or more CDRs (e.g., 1, 2, 3, 4, 5 or 6) and/or one or more variable domains as described herein is grafted, inserted, and/or joined. Chimeric Antibody, or an Antigen-Binding Fragment thereof [0658] In certain embodiments, the antibody, or antigen-binding fragment thereof, such as the antibody, or antigen-binding fragment thereof, which is the L moiety of compound 3.1, provided herein is a chimeric antibody. In some embodiments, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Certain chimeric antibodies are described, e.g., in U.S. Patent No. 4,816,567; and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA, 81 :6851-6855 (1984)). Chimeric antibodies include antigen-binding fragments thereof. Nonlimiting exemplary chimeric antibodies include chimeric antibodies comprising any of the heavy and/or light chain variable regions as described herein. Additional nonlimiting exemplary chimeric antibodies include chimeric antibodies comprising heavy chain CDR sequences or portions thereof, and/or light chain CDR sequences as provided herein. Humanized Antibody, or antigen-binding fragment thereof [0659] In certain embodiments, the antibody, or antigen-binding fragment thereof, is a humanized antibody, or antigen-binding fragment thereof, that binds gpNMB. Typically, a non-human antibody is humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody. A humanized antibody is a genetically engineered antibody in which the CDRs or portions thereof from a non-human “donor” antibody are grafted into human “acceptor” antibody sequences (see, e.g., Queen, US 5,530,101 and 5,585,089; Winter, US 5,225,539; Carter, US 6,407,213; Adair, US 5,859,205; and Foote, US 6,881,557). [0660] The acceptor antibody sequences can be, for example, a mature human antibody sequence, a composite of such sequences, a consensus sequence of human antibody sequences, or a germline region sequence. Human acceptor sequences can be selected for a high degree of sequence identity in the variable region frameworks with donor sequences to match canonical forms between acceptor and donor CDRs among other criteria. Thus, a humanized antibody is an antibody having CDRs entirely or substantially from a donor antibody and variable region framework sequences and constant regions, if present, entirely or substantially from human antibody sequences. Similarly, a humanized heavy chain typically has all three CDRs entirely or substantially from a donor antibody heavy chain, and a heavy chain variable region framework sequence and heavy chain constant region, if present, substantially from human heavy chain variable region framework and constant region sequences. Likewise, a humanized light chain usually has all three CDRs entirely or substantially from a donor antibody light chain, and a light chain variable region framework sequence and light chain constant region, if present, substantially from human light chain variable region framework and constant region sequences. A CDR in a humanized antibody is substantially from a corresponding CDR in a non-human antibody when at least 80%, 85%, 90%, 95% or 100% of corresponding residues (such as defined by Kabat) are identical between the respective CDRs. The variable region framework sequences of an antibody chain or the constant region of an antibody chain are substantially from a human variable region framework sequence or human constant region respectively when at least 80%, 85%, 90%, 95% or 100% of corresponding residues, such as defined by Kabat, are identical. [0661] For example, when an amino acid differs between a murine variable region framework residue and a selected human variable region framework residue, the human framework amino acid can be substituted by the equivalent framework amino acid from the mouse antibody when it is reasonably expected that the amino acid: (1) noncovalently binds antigen directly, (2) is adjacent to a CDR region, (3) otherwise interacts with a CDR region (e.g., is within about 6 Å of such a region); (4) mediates interaction between the heavy and light chains, or (5) is the result of somatic mutation in the mouse chain. (6) is a site of glycosylation. [0662] Framework residues from classes (1)-(3) are sometimes alternately referred to as canonical and vernier residues. Canonical residues refer to framework residues defining the canonical class of the donor CDR loops determining the conformation of a CDR loop (Chothia and Lesk, J. Mol. Biol. 196, 901-917 (1987), Thornton & Martin, J. Mol. Biol., 263, 800-815, 1996). Vernier residues refer to a layer of framework residues that support antigen- binding loop conformations and play a role in fine-tuning the fit of an antibody to antigen (Foote & Winter, 1992, J Mol Bio. 224, 487-499). [0663] Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, (2008) Front. Biosci. 13: 1619-1633, and are further described, e.g., in Riechmann et al., (1988) Nature 332:323-329; Queen et al., (1989) Proc. Natl Acad. Sci. USA 86: 10029-10033; US Patent Nos. 5, 821,337, 7,527,791, 6,982,321, and 7,087,409; Kashmiri et al., (2005) Methods 36:25-34 (describing specificity determining region (SDR) grafting); Padlan, (1991) Mol. Immunol. 28:489-498 (describing “resurfacing”); Dall'Acqua et al., (2005) Methods 36:43-60 (describing “FR shuffling”); and Osbourn et al., (2005) Methods 36:61-68 and Klimka et al., (2000) Br. J. Cancer, 83:252-260 (describing the “guided selection” approach to FR shuffling). [0664] Human framework regions that may be used for humanization include but are not limited to: framework regions selected using the “best-fit” method (see, e.g., Sims et al. (1993) J. Immunol. 151 :2296); framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions (see, e.g., Carter et al. (1992) Proc. Natl. Acad. Sci. USA, 89:4285; and Presta et al. (1993) J. Immunol, 151:2623); human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro and Fransson, (2008) Front. Biosci. 13:1619-1633); and framework regions derived from screening FR libraries (see, e.g., Baca et al., (1997) J. Biol. Chem. 272: 10678-10684 and Rosok et al., (1996) J. Biol. Chem. 271 :22611-22618). [0665] Non-limiting exemplary chimeric antibodies include chimeric antibodies comprising or derived from any of the CDR and/or heavy chain variable region and/or light chain variable regions as disclosed herein. . [0666] Although humanized antibodies often incorporate all six HVRs (e.g., CDRs, preferably as defined by Kabat) from a mouse antibody, they can also be made with less than all HVRs or CDRs (e.g., at least 3, 4, or 5) HVRs or CDRs from a mouse antibody (e.g., Pascalis et al., J. Immunol. 169:3076, 2002; Vajdos et al., Journal of Molecular Biology, 320: 415-428, 2002; Iwahashi et al., Mol. Immunol. 36:1079-1091, 1999; and Tamura et al, Journal of Immunology, 164:1432-1441, 2000). [0667] Certain amino acids from the human variable region framework residues can be selected for substitution based on their possible influence on HVR (e.g,.CDR) conformation and/or binding to antigen. Investigation of such possible influences is by modeling, examination of the characteristics of the amino acids at particular locations, or empirical observation of the effects of substitution or mutagenesis of particular amino acids. Exemplary Antibody Constant Regions [0668] In some embodiments, the heavy and light chain variable regions of antibodies, or antigen-binding fragments thereof, described herein can be linked to at least a portion of a human constant region. In some embodiments, the human heavy chain constant region is of an isotype selected from IgA, IgG, and IgD. In some embodiments, the human light chain constant region is of an isotype selected from κ and λ. In some embodiments, an antibody described herein comprises a human IgG constant region. In some embodiments, an antibody described herein comprises a human IgG4 heavy chain constant region. In some of these embodiments, an antibody described herein comprises an S241P mutation in the human IgG4 constant region. In some embodiments, an antibody described herein comprises a human IgG4 constant region and a human κ light chain. [0669] Throughout the present specification and claims unless explicitly stated or known to one skilled in the art, the numbering of the residues in an immunoglobulin heavy chain is that of the EU index as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991), expressly incorporated herein by reference. The “EU index as in Kabat” refers to the residue numbering of the human IgG1 EU antibody. [0670] Human constant regions show allotypic variation and isoallotypic variation between different individuals, that is, the constant regions can differ in different individuals at one or more polymorphic positions. Isoallotypes differ from allotypes in that sera recognizing an isoallotype binds to a non-polymorphic region of a one or more other isotypes. Reference to a human constant region includes a constant region with any natural allotype or any permutation of residues occupying polymorphic positions in natural allotypes. Also, up to 1, 2, 5, or 10 mutations may be present relative to a natural human constant region, such as those indicated above to reduce Fcγ receptor binding or increase binding to FcRn. [0671] In some embodiments, one or several amino acids at the amino or carboxy terminus of the light and/or heavy chain, such as the C-terminal lysine of the heavy chain, may be missing or derivatized in a proportion or all of the molecules. [0672] The choice of constant region depends, in part, whether antibody-dependent cell- mediated cytotoxicity, antibody dependent cellular phagocytosis and/or complement dependent cytotoxicity are desired. For example, human isotopes IgG1 and IgG3 have strong complement-dependent cytotoxicity, human isotype IgG2 weak complement-dependent cytotoxicity and human IgG4 lacks complement-dependent cytotoxicity. Human IgG1 and IgG3 also induce stronger cell-mediated effector functions than human IgG2 and IgG4. Light chain constant regions can be lambda or kappa. [0673] Furthermore, as described in greater detail below, substitutions can be made in the constant regions to reduce or increase effector function such as complement-mediated cytotoxicity or ADCC (see, e.g., Winter et al., US Patent No. 5,624,821; Tso et al., US Patent No. 5,834,597; and Lazar et al., Proc. Natl. Acad. Sci. USA 103:4005, 2006), or to prolong half-life in humans (see, e.g., Hinton et al., J. Biol. Chem. 279:6213, 2004). Variant Antibody or Antigen-Binding Fragments thereof [0674] The antibodies, or antigen-binding fragments thereof, provided herein also include amino acid sequence variants of the antibody, or antigen-binding fragment thereof, provided herein such as those described in Table D1 and D2. As an example, variants with improved binding affinity and/or other biological properties of the antibody can be prepared. Amino acid sequence variants of an antigen binding protein can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antigen binding protein, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antigen binding protein. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding. [0675] Substitution, insertion, and deletion variants. In some embodiments, an antibody, or antigen-binding fragment thereof, is a variant in that it has one or more amino acid substitutions, deletions and/or insertions relative to an antibody, or antigen-binding fragment thereof, as described herein (e.g., an antibody, or antigen-binding fragment thereof, having the amino acid sequences as described in Tables D1 and D2. In certain such embodiments, the variant has one or more amino acid substitutions. In further such embodiments, the substitutions are conservative amino acid substitutions. [0676] An amino acid substitution can include but are not limited to the replacement of one amino acid in a polypeptide with another amino acid. Conservative amino acid substitutions can encompass non-naturally occurring amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. Naturally occurring residues can be divided into classes based on common side chain properties. (1) hydrophobic: Norleucine, Met, Ala, Val, Leu, Ile; (2) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) acidic: Asp, Glu; (4) basic: His, Lys, Arg; (5) residues that influence chain orientation: Gly, Pro; (6) aromatic: Trp, Tyr, Phe. [0677] Sites of interest for substitutional mutagenesis include the CDRs and framework regions. Conservative substitutions are shown in Table D3, below, under the heading of "Preferred Substitutions." More substantial changes are provided in Table D3 under the heading of "Exemplary Substitutions," and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC. Table D3. Conservative and Exemplary Amino Acid Substitutions.
Figure imgf000286_0001
Figure imgf000287_0001
[0678] Non-conservative substitutions involve exchanging a member of one of these classes for another class. [0679] In altering the amino acid sequence of the antigen binding protein (e.g,. anti- gpNMB antibody or antigen-binding fragments thereof), in some embodiments the hydropathic index of amino acids can be considered. Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics as follows: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (-0.4); threonine (-0.7); serine (-0.8); tryptophan (- 0.9); tyrosine (-1.3); proline (-1.6); histidine (-3.2); glutamate (-3.5); glutamine (-3.5); aspartate (-3.5); asparagine (-3.5); lysine (-3.9); and arginine (-4.5). [0680] The importance of the hydropathic amino acid index in conferring interactive biological function on a protein is understood in the art. Kyte et al., 1982, J. Mol. Biol., 157:105-131. It is known that certain amino acids can be substituted for other amino acids having a similar hydropathic index or score and still retain a similar biological activity. In making changes based upon the hydropathic index, in certain embodiments, the substitution of amino acids whose hydropathic indices are within ± 2 is included. In certain embodiments, those which are within ± 1 are included, and in certain embodiments, those within ± 0.5 are included. [0681] It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity, particularly where the biologically functional protein or peptide (e.g., antibody) thus created is intended for use in immunological embodiments, as in the present case. In certain embodiments, the greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with its immunogenicity and antigenicity, i.e., with a biological property of the protein. [0682] The following hydrophilicity values have been assigned to these amino acid residues: arginine (+3.0); lysine (+3.0 ±1); aspartate (+3.0 ±1); glutamate (+3.0 ±1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (-0.4); proline (-0.5 ±1); alanine (-0.5); histidine (-0.5); cysteine (-1.0); methionine (-1.3); valine (-1.5); leucine (-1.8); isoleucine (-1.8); tyrosine (-2.3); phenylalanine (-2.5) and tryptophan (-3.4). In making changes based upon similar hydrophilicity values, in certain embodiments, the substitution of amino acids whose hydrophilicity values are within ± 2 is included, in certain embodiments, those which are within ± 1 are included, and in certain embodiments, those within ± 0.5 are included. One can also identify epitopes from primary amino acid sequences on the basis of hydrophilicity. These regions are also referred to as "epitopic core regions." [0683] Alterations (e.g., substitutions) can be made in CDRs, e.g., to improve antibody affinity. Such alterations can be made in CDR "hotspots," i.e., residues encoded by codons that undergo mutation at high frequency during the somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and/or residues that contact antigen, with the resulting variant VH or VL being tested for binding affinity. Affinity maturation by constructing and reselecting from secondary libraries has been described, e.g., in Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, N.J., (2001).) In some embodiments of affinity maturation, diversity is introduced into the variable genes chosen for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method to introduce diversity involves hypervariable region (HVR)- directed approaches, in which several HVR residues (e.g., 4-6 residues at a time) are randomized. HVR residues involved in antigen binding may be specifically identified, e.g., using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted. [0684] In certain embodiments, substitutions, insertions, or deletions can occur within one or more CDRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen. For example, conservative alterations (e.g., conservative substitutions as provided herein) that do not substantially reduce binding affinity may be made in CDRs. Such alterations may, for example, be outside of antigen contacting residues in the CDRs. In certain embodiments of the variant VH and VL sequences provided above, each CDR either is unaltered, or contains no more than one, two or three amino acid substitutions. [0685] A useful method for identification of residues or regions of an antibody that may be targeted for mutagenesis is called "alanine scanning mutagenesis" as described by Cunningham and Wells (1989) Science, 244:1081-1085. In this method, a residue or group of target residues (e.g., charged residues such as arg, asp, his, lys, and glu) are identified and replaced by a neutral or negatively charged amino acid (e.g., alanine or polyalanine) to determine whether the interaction of the antibody with antigen is affected. Further substitutions may be introduced at the amino acid locations demonstrating functional sensitivity to the initial substitutions. Alternatively, or additionally, a crystal structure of an antigen-antibody complex to identify contact points between the antibody and antigen. Such contact residues and neighboring residues may be targeted or eliminated as candidates for substitution. Variants may be screened to determine whether they contain the desired properties. [0686] Amino acid sequence insertions include amino- and/or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing a hundred or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include an antibody with an N-terminal methionyl residue. Other insertional variants of the antibody molecule include the fusion to the N- or C-terminus of the antibody to an enzyme (e.g. for ADEPT) or a polypeptide which increases the serum half-life of the antibody. Variants with Modified Fc Region [0687] Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Pat. No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called "DANA" Fc mutant with substitution of residues 265 and 297 to alanine (U.S. Pat. No. 7,332,581). [0688] In certain embodiments, an antibody variant is prepared that has improved or diminished binding to FcRs are described. (See, e.g., U.S. Pat. No. 6,737,056; WO 2004/056312, and Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001).) In some embodiments, an antibody variant comprises an Fc region with one or more amino acid substitutions which improve ADCC, e.g., substitutions at positions 298, 333, and/or 334 of the Fc region (EU numbering of residues). For instance, a systemic substitution of solvent- exposed amino acids of human IgG1 Fc region has generated IgG variants with altered FcγR binding affinities (Shields et al., 2001, J. Biol. Chem. 276:6591-604). When compared to parental IgG1, a subset of these variants involving substitutions at Thr256/Ser298, Ser298/Glu333, Ser298/Lys334, or Ser298/Glu333/Lys334 to Ala demonstrate increased in both binding affinity toward FcγR and ADCC activity (Shields et al., 2001, J. Biol. Chem. 276:6591-604; Okazaki et al., 2004, J. Mol. Biol. 336:1239-49). [0689] In some embodiments, alterations are made in the Fc region to alter (i.e., either improved or diminished) Clq binding and/or Complement Dependent Cytotoxicity (CDC), e.g., as described in U.S. Pat. No. 6,194,551, WO 99/51642, and Idusogie et al. J. Immunol. 164: 4178-4184 (2000). For instance, complement fixation activity of antibodies (both C1q binding and CDC activity) can be improved by substitutions at Lys326 and Glu333 (Idusogie et al., 2001, J. Immunol. 166:2571-2575). The same substitutions on a human IgG2 backbone can convert an antibody isotype that binds poorly to C1q and is severely deficient in complement activation activity to one that can both bind C1q and mediate CDC (Idusogie et al., 2001, J. Immunol. 166:2571-75). Several other methods have also been applied to improve complement fixation activity of antibodies. For example, the grafting of an 18- amino acid carboxyl-terminal tail piece of IgM to the carboxyl-termini of IgG greatly enhances their CDC activity. This is observed even with IgG4, which normally has no detectable CDC activity (Smith et al., 1995, J. Immunol. 154:2226-36). Also, substituting Ser444 located close to the carboxy-terminal of IgG1 heavy chain with Cys induced tail-to- tail dimerization of IgG1 with a 200-fold increase of CDC activity over monomeric IgG1 (Shopes et al., 1992, J. Immunol. 148:2918-22). In addition, a bispecific diabody construct with specificity for C1q also confers CDC activity (Kontermann et al., 1997, Nat. Biotech. 15:629-31). [0690] Complement activity can be reduced by mutating at least one of the amino acid residues 318, 320, and 322 of the heavy chain to a residue having a different side chain, such as Ala. Other alkyl-substituted non-ionic residues, such as Gly, Ile, Leu, or Val, or such aromatic non-polar residues as Phe, Tyr, Trp and Pro in place of any one of the three residues also reduce or abolish C1q binding. Ser, Thr, Cys, and Met can be used at residues 320 and 322, but not 318, to reduce or abolish C1q binding activity. Replacement of the 318 (Glu) residue by a polar residue may modify but not abolish C1q binding activity. Replacing residue 297 (Asn) with Ala results in removal of lytic activity but only slightly reduces (about three fold weaker) affinity for C1q. This alteration destroys the glycosylation site and the presence of carbohydrate that is required for complement activation. Any other substitution at this site also destroys the glycosylation site. The following mutations and any combination thereof also reduce C1q binding: D270A, K322A, P329A, and P311S (see WO 06/036291). [0691] The half-life of an antibody as provided herein can be increased or decreased to modify its therapeutic activities. FcRn is a receptor that is structurally similar to MHC Class I antigen that non-covalently associates with β2-microglobulin. FcRn regulates the catabolism of IgGs and their transcytosis across tissues (Ghetie and Ward, 2000, Annu. Rev. Immunol. 18:739-766; Ghetie and Ward, 2002, Immunol. Res. 25:97-113). The IgG-FcRn interaction takes place at pH 6.0 (pH of intracellular vesicles) but not at pH 7.4 (pH of blood); this interaction enables IgGs to be recycled back to the circulation (Ghetie and Ward, 2000, Ann. Rev. Immunol. 18:739-766; Ghetie and Ward, 2002, Immunol. Res. 25:97-113). The region on human IgG1 involved in FcRn binding has been mapped (Shields et al., 2001, J. Biol. Chem. 276:6591-604). Alanine substitutions at positions Pro238, Thr256, Thr307, Gln311, Asp312, Glu380, Glu382, or Asn434 of human IgG1 enhance FcRn binding (Shields et al., 2001, J. Biol. Chem. 276:6591-604). IgG1 molecules harboring these substitutions have longer serum half-lives. Consequently, these modified IgG1 molecules may be able to carry out their effector functions, and hence exert their therapeutic efficacies, over a longer period of time compared to unmodified IgG1. Other exemplary substitutions for increasing binding to FcRn include a Gln at position 250 and/or a Leu at position 428. Other studies have shown that binding of the Fc region to FcRn can be improved by introducing one or more substitutions at one or more the following Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311, 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (see, e.g., U.S. Pat. No. 7,371,826; and US 7,361,740). Antibody Variants with Modified Glycosylation [0692] In certain embodiments, an antibody, or antigen-binding fragment thereof, as provided herein includes one or more modifications so as to increase or decrease the extent to which the antibody is glycosylated. Addition or deletion of glycosylation sites to an antibody can be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed. [0693] Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered. Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. TIBTECH 15:26-32 (1997). The oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the "stem" of the biantennary oligosaccharide structure. [0694] Engineering of this glycoform on IgG can significantly improve IgG-mediated ADCC. Addition of bisecting N-acetylglucosamine modifications (Umana et al., 1999, Nat. Biotechnol. 17:176-180; Davies et al., 2001, Biotech. Bioeng. 74:288-94) to this glycoform or removal of fucose (Shields et al., 2002, J. Biol. Chem. 277:26733-40; Shinkawa et al., 2003, J. Biol. Chem. 278:6591-604; Niwa et al., 2004, Cancer Res. 64:2127-33) from this glycoform are two examples of IgG Fc engineering that improves the binding between IgG Fc and FcγR, thereby enhancing Ig-mediated ADCC activity. Antibodies including such substitutions or engineering are included in some of the embodiments provided herein. [0695] In certain embodiments, antibodies are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region. For example, the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%. The amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e.g., complex, hybrid and high mannose structures) as measured by MALDI-TOF mass spectrometry, as described in WO 2008/077546, for example. Asn297 refers to the asparagine residue located at about position 297 in the Fc region (EU numbering of Fc region residues); however, Asn297 may also be located about ± 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO2002/031140; Okazaki et al. J. Mol. Biol. 336:1239-1249 (2004); Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies include Lec13 CHO cells deficient in protein fucosylation (Ripka et al. Arch. Biochem. Biophys. 249:533-545 (1986); US Patent Application No. US 2003/0157108 A1, Presta, L; and WO 2004/056312 A1, Adams et al., especially at Example 11), and knockout cell lines, such as alpha-1,6-fucosyltransferase gene, FUT8, knockout CHO cells (see, e.g., Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004); Kanda, Y. et al., Biotechnol. Bioeng., 94(4):680-688 (2006); and WO2003/085107). [0696] Other antibodies are further provided which contain bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibodies may have reduced fucosylation and/or improved ADCC function. Examples of such antibodies are described, e.g., in WO 2003/011878 (Jean- Mairet et al.); US Patent No. 6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibodies with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided. Such antibody variants may have improved CDC function. Such antibody variants are described, e.g., in WO 1997/30087 (Patel et al.); WO 1998/58964 (Raju, S.); and WO 1999/22764 (Raju, S.). Cysteine Engineered Antibody Variants [0697] In some embodiments, an antibody variant as provided herein includes a substitution of the native amino acid to a cysteine residue at amino acid position 234, 235, 237, 239, 267, 298, 299, 326, 330, or 332, preferably an S239C mutation (substitutions of the constant regions are according to the EU index) in a human IgG1 isotype. The presence of an additional cysteine residue allows interchain disulfide bond formation. Such interchain disulfide bond formation can cause steric hindrance, thereby reducing the affinity of the Fc region-FcγR binding interaction. The cysteine residue(s) introduced in or in proximity to the Fc region of an IgG constant region can also serve as sites for conjugation to therapeutic agents (e.g., coupling cytotoxic drugs using thiol specific reagents such as maleimide derivatives of drugs). The presence of a therapeutic agent causes steric hindrance, thereby further reducing the affinity of the Fc region-FcγR binding interaction. Other substitutions at any of positions 234, 235, 236 and/or 237 reduce affinity for Fcγ receptors, particularly FcγRI receptor (see, e.g., US 6,624,821, US 5,624,821.) [0698] In other cysteine engineered antibody variants, one or more reactive thiol groups are positioned at accessible sites of the antibody and can be used to conjugate the antibody to other moieties, such as drug moieties or linker-drug moieties, to create an immunoconjugate, as described further herein. In certain embodiments, any one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of the light chain; A118 (EU numbering) of the heavy chain; and 5400 (EU numbering) of the heavy chain Fc region. Generating of cysteine engineered antibodies are described, e.g., in U.S. Pat. No. 7,521,541. Competing Antibody, or Antigen-Binding Fragments thereof [0699] The antibodies, or antigen-binding fragments thereof, provided herein include those that compete with one of the exemplified antibodies, or antigen-binding fragment thereof, for specific binding, such as to gpNMB, such as human gpNMB. In some of these embodiments, the test and reference antibody, or antigen-binding fragment thereof, cross- compete with one another. Such an antibody, or antigen-binding fragments thereof, may bind to the same epitope as one of the antibodies, or antigen-binding fragments thereof, described herein, or to an overlapping epitope. Antibodies, or antigen-binding fragments thereof, are expected to show similar functional properties (e.g., one or more of the activities described above). The exemplified antibody, or antigen-binding fragment thereof, include those described above, including those with: 1) the heavy and/or light chains, 2) VHs and/or VLs, and/or 3) that comprise one or more of the CDRs included in Tables D1 and D2. [0700] Thus, in some embodiments, the antibody, or antigen-binding fragment thereof, that are provided include those that compete with an antibody having: (a) all 6 of the CDRs listed for the antibody described in Table D1; (b) a VH and a VL listed for the antibody described in Table D2; or (c) the light chain and heavy chain as specified for the antibody described in Table D2. [0701] In some embodiments, competition or cross-competition is determined by surface plasmon resonance analysis (e.g., BIACORE®) (see, e.g., Abdiche, et al., 2009, Anal. Biochem. 386:172-180; Abdiche, et al., 2012, J. Immunol Methods 382:101-116; and Abdiche, et al., 2014 PLoS One 9:e92451. Ligand-Drug Conjugate Mixtures and Compositions [0702] The present invention provides Ligand-Drug Conjugate mixtures and pharmaceutical compositions comprising any of the Ligand-Drug Conjugates described herein. The mixtures and pharmaceutical compositions comprise a plurality of conjugates. In some embodiments, each of the conjugates in the mixture or composition is identical or substantially identical, however, the distribution of drug-linkers on the ligands in the mixture or compositions may vary as well as the drug loading. For example, the conjugation technology used to conjugate drug-linkers to antibodies as the targeting agent in some embodiments results in a composition or mixture that is heterogeneous with respect to the distribution of Drug-Linker compounds on the antibody (Ligand Unit) within the mixture and/or composition. In some of those embodiments, the loading of Drug-Linker compounds on each of the antibody molecules in a mixture or composition of such molecules is an integer that ranges from 1 to 16. [0703] In those embodiments, when referring to the composition as a whole, the loading of drug-linkers is a number ranging from 1 to about 16. Within the composition or mixture, there sometimes is a small percentage of unconjugated antibodies. The average number of drug-linkers per Ligand Unit in the mixture or composition (i.e., average drug-load) is an important attribute as it determines the maximum amount of drug that is delivered to the target cell. Typically, the average drug load is 1, 2 or about 2, 3 or about 3, 4 or about 4, 5 or about 5, 6 or about 6, 7 or about 7, 8 or about 8, 9 or about 9, 10 or about 10, 11 or about 11, 12 or about 12, 13 or about 13, 14 or about 14, 15 or about 15, 16 or about 16. In some embodiments, the average drug loading is from about 1 to about 16, from about 2 to about 12, from about 3 to about 8, or about 4. In some embodiments, the average drug loading is from about 3 to about 5, from about 3.5 to about 4.5, from about 3.7 to about 4.3, from about 3.9 to about 4.3, or about 4. [0704] In some embodiments, the mixtures and pharmaceutical compositions comprise a plurality (i.e., population) of conjugates, however, the conjugates are identical or substantially identical and are substantially homogenous with respect to the distribution of drug-linkers on the ligand molecules within the mixture and/or composition and with respect to loading of drug-linkers on the ligand molecules within the mixture and/or composition. In some such embodiments, the loading of drug-linkers on an antibody Ligand Unit is 2 or 4. Within the composition or mixture, there may also be a small percentage of unconjugated antibodies. The average drug load in such embodiments is about 2 or about 4. Typically, such compositions and mixtures result from the use of site-specific conjugation techniques and conjugation is due to an introduced cysteine residue. [0705] The average number of Drug Units or Drug-Linker compounds per Ligand Unit in a preparation from a conjugation reaction may be characterized by conventional means such as mass spectrometry, ELISA assay, HPLC (e.g., HIC). In those instances, the quantitative distribution of Ligand-Drug Conjugates in terms of subscript p may also be determined. In other instances, separation, purification, and characterization of homogeneous Ligand-Drug Conjugates may be achieved by conventional means such as reverse phase HPLC or electrophoresis. [0706] In some embodiments, the compositions are pharmaceutical compositions comprising the Ligand-Drug Conjugates described herein and a pharmaceutically acceptable carrier. In some of those embodiments, the pharmaceutical composition is in liquid form. In some embodiments, the pharmaceutical composition is a solid. In other of those embodiments, the pharmaceutical composition is a lyophilized powder. [0707] The compositions, including pharmaceutical compositions, are provided in purified form. As used herein, “purified” means that when isolated, the isolate contains at least 95%, and in other embodiments at least 98%, of Conjugate by weight of the isolate. Methods of Use Treatment of Cancer [0708] The Ligand-Drug Conjugates are useful for inhibiting the multiplication of a tumor cell or cancer cell, causing apoptosis in a tumor or cancer cell, or for treating a cancer in a patient. The Ligand-Drug Conjugates are used accordingly in a variety of settings for the treatment of cancers. The Ligand-Drug Conjugates are intended to deliver a drug to a tumor cell or cancer cell. Without being bound by theory, in one embodiment, the Ligand Unit of a Ligand-Drug Conjugate binds to or associates with a cancer-cell or a tumor-cell-associated antigen, and the Ligand-Drug Conjugate is taken up (internalized) inside the tumor cell or cancer cell through receptor-mediated endocytosis or other internalization mechanism. In some embodiments, the antigen is attached to a tumor cell or cancer cell or is an extracellular matrix protein associated with the tumor cell or cancer cell. Once inside the cell, via activation of the Activation Unit, the drug is released within the cell. In an alternative embodiment, the free drug is released from the Ligand-Drug Conjugate outside the tumor cell or cancer cell, and the free drug subsequently penetrates the cell. [0709] In one embodiment, the Ligand Unit binds to the tumor cell or cancer cell. [0710] In another embodiment, the Ligand Unit binds to a tumor cell or cancer cell antigen which is on the surface of the tumor cell or cancer cell. [0711] In another embodiment, the Ligand Unit binds to a tumor cell or cancer cell antigen that is an extracellular matrix protein associated with the tumor cell or cancer cell. [0712] The specificity of the Ligand Unit for a particular tumor cell or cancer cell is an important consideration for determining the tumors or cancers that are most effectively treated. For example, Ligand-Drug Conjugates that target a cancer cell antigen present on hematopoietic cancers are useful treating hematologic malignancies (e.g., anti-CD30, anti- CD70, anti-CD19, anti-CD33 binding Ligand Unit (e.g., antibody) are useful for treating hematologic malignancies). Ligand-Drug Conjugates that target a cancer cell antigen present on solid tumors in some embodiments are useful treating such solid tumors. [0713] Cancers that are intended to be treated with a Drug-Linker Conjugate include, but are not limited to, hematopoietic cancers such as, for example, lymphomas (Hodgkin Lymphoma and Non-Hodgkin Lymphomas) and leukemias and solid tumors. Examples of hematopoietic cancers include, follicular lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, acute myeloblastic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, diffuse large B cell lymphoma, and multiple myeloma. Examples of solid tumors include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, and retinoblastoma. [0714] In some embodiments, the treated cancer is any one of the above-listed lymphomas and leukemias. Multi-Modality Therapy for Cancer [0715] Cancers, including, but not limited to, a tumor, metastasis, or other disease or disorder characterized by uncontrolled cell growth are intended to be treated or inhibited by administration of an effective amount of a Ligand-Drug Conjugate. [0716] In one group of embodiments, methods for treating cancer are provided, including administering to a patient in need thereof an effective amount of a Ligand-Drug Conjugate and a chemotherapeutic agent. In one embodiment the chemotherapeutic agent is one in which treatment of the cancer has not been found to be refractory to that agent. In another embodiment, the chemotherapeutic agent one in which the treatment of cancer has been found to be refractory to that agent. [0717] In another group of embodiments, the Ligand-Drug Conjugates is administered to a patient that has also undergone surgery as treatment for the cancer. In such embodiments a chemotherapeutic agent is typically administered over a series of sessions, or one or a combination of the chemotherapeutic agents, such a standard of care chemotherapeutic agent(s), is administered. [0718] In either group of embodiments, the patient also receives an additional treatment, such as radiation therapy. In a specific embodiment, the Ligand-Drug Conjugate is administered concurrently with the chemotherapeutic agent or with radiation therapy. In another specific embodiment, the chemotherapeutic agent or radiation therapy is administered prior or subsequent to administration of a Ligand-Drug Conjugate. [0719] Additionally, methods of treatment of cancer with a Ligand-Drug Conjugate are provided as an alternative to chemotherapy or radiation therapy where the chemotherapy or the radiation therapy has proven or can prove too toxic, e.g., results in unacceptable or unbearable side effects, for the subject being treated. The patient being treated is optionally treated with another cancer treatment such as surgery, radiation therapy or chemotherapy, depending on which treatment is found to be acceptable or bearable. Treatment of Autoimmune Diseases [0720] The Ligand-Drug Conjugates are intended to be useful for killing or inhibiting the unwanted replication of cells that produce an autoimmune disease or for treating an autoimmune disease. [0721] The Ligand-Drug Conjugates are used accordingly in a variety of settings for the treatment of an autoimmune disease in a patient. The Ligand-Drug Conjugates are typically used to deliver a Drug Unit to a target cell. Without being bound by theory, in one embodiment, the Ligand-Drug Conjugate associates with an antigen on the surface of a pro- inflammatory or inappropriately stimulated immune cell, and the Ligand-Drug Conjugate is then taken up inside the targeted cell through receptor-mediated endocytosis. Once inside the cell, the Linker Unit is cleaved, resulting in release of the Drug Unit as free drug. The free drug is then able to migrate within the cytosol and induce a cytotoxic or cytostatic activity. In an alternative embodiment, the Drug Unit is cleaved from the Ligand-Drug Conjugate outside the target cell, and the free drug resulting from that release subsequently penetrates the cell. [0722] In one embodiment, the Ligand Unit binds to an autoimmune antigen. In one such embodiment, the antigen is on the surface of a cell involved in an autoimmune condition. [0723] In one embodiment, the Ligand Unit binds to activated lymphocytes that are associated with the autoimmune disease state. [0724] In a further embodiment, the Ligand-Drug Conjugate kills or inhibits the multiplication of cells that produce an autoimmune antibody associated with a particular autoimmune disease. [0725] Particular types of autoimmune diseases intended to be treated with the Ligand- Drug Conjugates include, but are not limited to, Th2 lymphocyte related disorders (e.g., atopic dermatitis, atopic asthma, rhinoconjunctivitis, allergic rhinitis, Omenn’s syndrome, systemic sclerosis, and graft versus host disease); Th1 lymphocyte-related disorders (e.g., rheumatoid arthritis, multiple sclerosis, psoriasis, Sjorgren’s syndrome, Hashimoto’s thyroiditis, Grave’s disease, primary biliary cirrhosis, Wegener’s granulomatosis, and tuberculosis); and activated B lymphocyte-related disorders (e.g., systemic lupus erythematosus, Goodpasture’s syndrome, rheumatoid arthritis, and type I diabetes). Multi-Drug Therapy of Autoimmune Diseases [0726] Methods for treating an autoimmune disease are also disclosed including administering to a patient in need thereof an effective amount of a Ligand-Drug Conjugate and another therapeutic agent known for the treatment of an autoimmune disease. For any of the methods of treatment described herein, the Ligand-Drug Conjugate compound may be administered to a subject who is unable to tolerate another Ligand-Drug Conjugate compound in therapeutically effective doses. In some embodiments, the other Ligand-Drug Conjugate compound comprises monomethyl auristain E (MMAE) or monomethyl auristatin F (MMAF). In some embodiments, the patient has greater tolerance for a Ligand-Drug Conjugate compound provided herein as compared to another Ligand-Drug Conjugate compound (e.g., a Ligand-Drug Conjugate compound comprising MMAE or MMAF). Tolerability may be determined using known methods or any of the methods decribed herein. Compositions and Methods of Administration [0727] The present invention provides pharmaceutical compositions comprising the Ligand-Drug Conjugates described herein and at least one pharmaceutically acceptable carrier. The pharmaceutical composition is in any form that allows the compound to be administered to a patient for treatment of a disorder associated with expression of the antigen to which the Ligand unit binds. For example, the conjugates are in the form of a liquid or solid. The preferred route of administration is parenteral. Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In one embodiment, the pharmaceutical compositions is administered parenterally. In one embodiment, the conjugates are administered intravenously. Administration is by any convenient route, for example by infusion or bolus injection. [0728] Pharmaceutical compositions are formulated to allow a Ligand-Drug Conjugate to be bioavailable upon administration of the composition to a patient. Compositions sometimes take the form of one or more dosage units. [0729] Materials used in preparing the pharmaceutical compositions are preferably non- toxic in the amounts used. It will be evident to those of ordinary skill in the art that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of animal (e.g., human), the particular form of the compound, the manner of administration, and the composition employed. [0730] The composition in some embodiments is in the form of a liquid. The liquid in some of those embodiments is useful for delivery by injection. In some embodiments a composition for administration by injection, in addition to the Ligand-Drug Conjugate, contains one or more excipients selected from the group consisting of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent. [0731] The liquid compositions, whether they are solutions, suspensions or other like form, in some embodiments include one or more of the following: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which can serve as the solvent or suspending medium, polyethylene glycols, glycerin, cyclodextrin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as amino acids, acetates, citrates or phosphates; detergents, such as nonionic surfactants, polyols; and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition is sometimes enclosed in ampoule, a disposable syringe or a multiple-dose vial made of glass, plastic or other material. Physiological saline is an exemplary adjuvant. An injectable composition is preferably sterile. [0732] The amount of the conjugate that is effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, which in some embodiments is determined by standard clinical techniques. In addition, in vitro or in vivo assays are optionally employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient’s circumstances. [0733] The compositions comprise an effective amount of a Ligand-Drug Conjugate such that a suitable dosage amount will be obtained. Typically, that amount is at least about 0.01% of a compound by weight of the composition. [0734] For intravenous administration, the pharmaceutical composition typically comprises from about 0.01 to about 100 mg of a Ligand-Drug Conjugate per kg of the animal’s body weight. In one embodiment, the composition can include from about 1 to about 100 mg of a Ligand-Drug Conjugate per kg of the animal’s body weight. In another aspect, the amount administered will be in the range from about 0.1 to about 25 mg/kg of body weight of a compound. In some aspects, depending on the drug used, the dosage is even lower, for example, 1.0 µg/kg to 5.0 mg/kg, 4.0 mg/kg, 3.0 mg/kg, 2.0 mg/kg or 1.0 mg/kg, or 1.0 µg/kg to 500.0 µg/kg of the subject’s body weight. [0735] Generally, the dosage of a conjugate administered to a patient is typically about 0.01 mg/kg to about 100 mg/kg of the subject’s body weight or from 1.0 µg/kg to 5.0 mg/kg of the subject’s body weight. In some embodiments, the dosage administered to a patient is between about 0.01 mg/kg to about 15 mg/kg of the subject’s body weight. In some embodiments, the dosage administered to a patient is between about 0.1 mg/kg and about 15 mg/kg of the subject’s body weight. In some embodiments, the dosage administered to a patient is between about 0.1 mg/kg and about 20 mg/kg of the subject’s body weight. In some embodiments, the dosage administered is between about 0.1 mg/kg to about 5 mg/kg or about 0.1 mg/kg to about 10 mg/kg of the subject’s body weight. In some embodiments, the dosage administered is between about 1 mg/kg to about 15 mg/kg of the subject’s body weight. In some embodiments, the dosage administered is between about 1 mg/kg to about 10 mg/kg of the subject’s body weight. In some embodiments, the dosage administered is between about 0.1 to 4 mg/kg, even more preferably 0.1 to 3.2 mg/kg, or even more preferably 0.1 to 2.7 mg/kg of the subject’s body weight over a treatment cycle. [0736] The term “carrier” refers to a diluent, adjuvant or excipient, with which a compound is administered. Such pharmaceutical carriers in some embodiments is a liquid, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil. Other carriers include saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea. In addition, auxiliary, stabilizing, thickening, lubricating and coloring agents are sometimes used. In one embodiment, when administered to a patient, the Ligand-Drug Conjugate or compositions thereof and pharmaceutically acceptable carriers are sterile. [0737] Water is an exemplary carrier when the compounds are administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are often employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol. The present compositions, if desired, also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. [0738] In an embodiment, the conjugates are formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to animals, particularly human beings. Typically, the carriers or vehicles for intravenous administration are sterile isotonic aqueous buffer solutions. Where necessary, the compositions include a solubilizing agent. Compositions for intravenous administration optionally comprise a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachets indicating the quantity of active agent. Where a conjugate is to be administered by infusion, it is typically dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. In some aspects, where the conjugate is administered by injection, an ampoule of sterile water for injection or saline is sometimes provided and the ingredients are mixed prior to administration. [0739] The pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration. Methods of Preparing Drug-Linker compounds and Ligand-Drug Conjugate compounds [0740] Provided herein are methods for preparing Drug-Linker compounds from the auristatin compounds provided herein. In addition to the methods recited below, method of preparing Drug-Linker compounds from auristatin compounds will be well known to a person of skill in the art. [0741] Provided herein are methods for preparing Ligand-Drug Conjugate compounds from the auristatin compounds and Drug-Linker compounds provided herein. Methods for preparing the Ligand-Drug Conjugate compounds will be well known to a person of skill in the art. EXAMPLES [0742] General Information Chemical Synthesis. All commercially available anhydrous solvents and reagents were used without further purification. UPLC-MS system 1 consisted of a Waters SQ mass detector 2 interfaced to an Acquity Ultra Performance LC equipped with a CORTECS UPLC C182.1 x 50 mm, 1.6 µm reverse phase column. The acidic mobile phase (0.1% formic acid) consisted of a gradient of 3% acetonitrile/97% water to 100% acetonitrile (flow rate = 0.5 mL/min). Preparative HPLC was carried out on a Waters 2545 Binary Gradient Module with a Waters 2998 Photodiode Array Detector. Products were purified over a C12 Phenomenex Synergi 250 x 10.0 mm, 4 μm, 80 Å reverse phase column (<10 mg scale) or a C12 Phenomenex Synergi 250 x 50 mm, 10 μm, 80 Å reverse phase column (10-100 mg scale) eluting with 0.1% trifluoroacetic acid in water (solvent A) and 0.1% trifluoroacetic acid in acetonitrile (solvent B). The purification methods generally consisted of linear gradients of solvent A to solvent B, ramping from 90% aqueous solvent A to 5% solvent A. The flow rate was 4.6 mL/min with monitoring at 220 nm. NMR spectral data were collected on a Varian Mercury 400 MHz spectrometer. Coupling constants (J) are reported in hertz. [0743] Throughout the Examples, reference is made to the following structures: MMAE:
Figure imgf000304_0001
Example 1. General procedure for solid-phase/solution-phase synthesis of auristatins [0744] A similar procedure for Fmoc deprotection, amide coupling, alkylation and resin cleavage has been published (Moquist, P. N. et al. Mol. Cancer Ther. 2021, 20, 320-328).
Figure imgf000305_0001
Example 2. General Procedure for resin loading. [0745] 2-chlorotrityl resin (100-200 mesh), 1% DVB (Millipore Sigma, 855017) was loaded into a vessel and DCM (5V) was added to swell the resin for 30 min. The solvent was removed, and the resin was treated with solution of Fmoc-Dap (1 equivalent to resin loading) in DMF and DCM (1:1, 10V) and shaken for 2 h. The solution was filtered, and the resin resin washed with DMF (3 × 3 min), DCM (3 × 3 min), and Et2O (3 × 3 min) and vacuum- dried in a desiccator. Example 3. General procedure for Fmoc deprotection [0746] The resin was treated with a solution of piperidine in DMF (1:4 V/V) and shaken for 30 min. The solution was removed, and the resin was resubjected three additional times to the same conditions. The solution was filtered, and the resin are washed with DMF (3 × 3 min). Example 4. General procedure for amide coupling [0747] Fmoc-amino acid (2 equiv) was dissolved in dry DMF (0.2 M final concentration). DIPEA (4 equiv) and HATU (1.9 equiv) were added successively, and the reaction was stirred for 5 min. The resin was treated with the solution of activated Fmoc-amino acid and shaken for 2 h. The solution was filtered, and the resin was washed with DMF (3 × 3 min). Example 5. General procedure for resin cleavage [0748] Prior to cleavage the resin was washed with DCM (3 × 3 min). Resin was cleaved with a solution of 20:80 (V/V) solution of HFIP/ DCM (10 min). Solution is removed in vacuo, and crude was dissolved for UPLC analysis and preparative HPLC. HPLC fraction were frozen and dried by lyophilization. Example 6. General procedure for reductive alkylation [0749] Aldehyde (5 equiv.) was dissolved in a 0.6 mL solution of 1% (V/V) AcOH in DMF, followed by the addition of NaBH3CN (4 equiv.). The resin was treated with the solution and shaken for 2 h. The solution was filtered, and the resin was washed with DMF (3 × 3 mL) and DCM (3 × 3 mL) and vacuum-dried in a desiccator. Example 7. General procedure for C-terminal amine coupling [0750] Tetrapeptide (1 equiv) was dissolved in dry DMF (0.3 M final concentration). DIPEA (4 equiv) and HATU (0.95 equiv) were added successively, and the reaction was stirred for 15 min. The P5 amine was added to the activated ester and the reaction was stirred for 2 h. The solvent was removed in vacuo and purified by preparative HPLC. HPLC fractions were frozen and dried by lyophilization. Auristatin compounds [0751] Examples 8 to 33 were synthesized according to the procedures of Examples 1 to 7. Example 8.
Figure imgf000306_0001
[0752] Compound 1.1 was prepared by dimethylation of tetrapeptide and amide coupling of tetrapeptide with L-phenylalaninol. Analytical UPLC-MS: tR = 1.33 min, m/z (ES+) 720.49 (M+H)+, found 720.85. Example 9.
Figure imgf000307_0001
[0753] Compound 1.3 was prepared by dimethylation of tetrapeptide and amide coupling of tetrapeptide with L-phenylalaninol. Analytical UPLC-MS: tR = 1.16 min, m/z (ES+) 734.50 (M+H)+, found 734.49. Example 10.
Figure imgf000307_0002
[0754] Compound 1.4 was prepared by dimethylation of tetrapeptide and amide coupling of tetrapeptide with (1S,2R)-(+)-norephedrine. Analytical UPLC-MS: tR = 1.29 min, m/z (ES+) 734.50 (M+H)+, found 734.48. Example 11.
Figure imgf000307_0003
[0755] Compound 1.2 was prepared by dimethylation of tetrapeptide and amide coupling of tetrapeptide with (1S,2R)-(+)-norephedrine. Analytical UPLC-MS: tR = 1.26 min, m/z (ES+) 720.48 (M+H)+, found 720.51. Example 12.
Figure imgf000308_0001
[0756] Compound 1.9 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS: tR = 1.30 min, m/z (ES+) 706.47 (M+H)+, found 707.62. Example 13.
Figure imgf000308_0002
[0757] Compound 1.12 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS: tR = 1.40 min, m/z (ES+) 719.48 (M+H)+, found 720.99. Example 14.
Figure imgf000308_0003
[0758] Compound 1.10 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS: tR = 1.27 min, m/z (ES+) 706.47 (M+H)+, found 706.57. Example 15.
Figure imgf000308_0004
[0759] Compound 1.13 was prepared by reductive alkylation of tetrapeptide with acetaldehyde followed by amide coupling of tetrapeptide with L-phenylalaninol. Analytical UPLC-MS: tR = 1.21 min, m/z (ES+) 720.49 (M+H)+, found 720.57. Example 16.
Figure imgf000309_0001
[0760] Compound 1.11 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS: tR = 1.47 min, m/z (ES+) 734.51 (M+H)+, found 734.85. Example 17.
Figure imgf000309_0002
[0761] Compound 1.29 was prepared by amide coupling of tetrapeptide with (1S,2R)-(+)- norephedrine. Analytical UPLC-MS: tR = 1.58 min, m/z (ES+) 728.46 (M+Na)+, found 728.73. Example 18.
Figure imgf000309_0003
[0762] Compound 1.30 was prepared by amide coupling of tetrapeptide with phenethylamine. Analytical UPLC-MS: tR = 1.70 min, m/z (ES+) 698.45 (M+Na)+, found 698.50. Example 19.
Figure imgf000309_0004
[0763] Compound 1.32 was prepared by amide coupling of tetrapeptide with S- dolaphenine. Analytical UPLC-MS: tR = 1.85 min, m/z (ES+) 759.45 (M+H)+, found 760.05. Example 20.
Figure imgf000310_0001
[0764] Compound 1.33 was prepared by amide coupling of tetrapeptide with S- dolaphenine. Analytical UPLC-MS: tR = 1.89 min, m/z (ES+) 773.46 (M+H)+, found 773.58. Example 21.
Figure imgf000310_0002
[0765] N-terminal amino acid Fmoc-(N-methyl)-L-h-serine was synthesized from L-h- Serine(OtBu)-OH by reaction with formaldehyde (37% aqueous, 1.5 equiv), NaH2PO4 (2 equiv) in water, Zn (dust, 2 equiv), and AcOH (1 equiv.) at RT overnight similar to known procedure (Da Silva, R. A. et al. Tetrahedron Lett. 2007, 48, 7680-7682). Fmoc protecting group was then installed as described in a reported procedure (Wuts, P; Green, T. "Protective Groups in Organic Synthesis” New York, 2006). [0766] Compound 1.14 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS: tR = 1.13 min, m/z (ES+) 720.45 (M+H)+, found 720.49. Example 22.
Figure imgf000310_0003
[0767] N-terminal amino acid Fmoc-(N-methyl)-βh-threonine was synthesized from βh- threonine-(OtBu)-OH by reaction with formaldehyde (37% aqueous, 1.5 equiv), NaH2PO4 (2 equiv) in water, Zn (dust, 2 equiv) and AcOH (1 equiv.) at RT overnight similar to known procedure (Da Silva, R. A. et al. Tetrahedron Lett. 2007, 48, 7680-7682). Fmoc protecting group was then installed as described in a reported procedure (Wuts, P; Green, T. "Protective Groups in Organic Synthesis” New York, 2006). [0768] Compound 1.58 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS: tR = 1.20 min, m/z (ES+) 734.50 (M+H)+, found 734.52. Example 23.
Figure imgf000311_0001
[0769] Compound 1.16 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS: tR = 1.38 min, m/z (ES+) 692.46 (M+H)+, found 692.93. Example 24.
Figure imgf000311_0002
[0770] Compound 1.18 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS: tR = 1.37 min, m/z (ES+) 706.47 (M+H)+, found 706.55. Example 25.
Figure imgf000311_0003
[0771] Compound 1.20 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS: tR = 1.30 min, m/z (ES+) 706.47 (M+H)+, found 706.39. Example 26.
Figure imgf000312_0001
[0772] Compound 1.72 was prepared by amide coupling of tetrapeptide with (1S,2R)-(+)- norephedrine. Analytical UPLC-MS: tR = 1.19 min, m/z (ES+) 692.46 (M+H)+, found 692.49. Example 27.
Figure imgf000312_0002
[0773] Compound 1.22 was prepared by amide coupling of tetrapeptide with (1S,2R)-(+)- norephedrine. Analytical UPLC-MS: tR = 1.25 min, m/z (ES+) 706.47 (M+H)+, found 706.56. Example 28.
Figure imgf000312_0003
[0774] Compound 1.23repared by amide coupling of tetrapeptide with (1S,2R)-(+)- norephedrine. Analytical UPLC-MS: tR = 1.28 min, m/z (ES+) 720.48 (M+H)+, found 720.76. Example 29.
Figure imgf000312_0004
[0775] Compound 1.21 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS: tR = 1.30 min, m/z (ES+) 720.49 (M+H)+, found 720.85. Example 30.
Figure imgf000313_0001
[0776] Compound 1.24 was prepared by amide coupling of tetrapeptide with L-tyrosinol. Analytical UPLC-MS: tR = 1.15 min, m/z (ES+) 736.49 (M+H)+, found 736.79. Example 31.
Figure imgf000313_0002
[0777] Compound 1.25 was prepared by amide coupling of tetrapeptide with S- dolaphenine. Analytical UPLC-MS: tR = 1.49 min, m/z (ES+) 773.04 (M+H)+, found 773.61. Example 32.
Figure imgf000313_0003
[0778] Compound 1.56 was prepared by amide coupling of tetrapeptide with (1S,2R)-(+)- norephedrine. Analytical UPLC-MS: tR = 1.25 min, m/z (ES+) 706.48 (M+H)+, found 706.80. Example 33.
Figure imgf000313_0004
[0779] Compound 1.59 was prepared by amide coupling of tetrapeptide with (1S,2R)-(+)- norephedrine. Analytical UPLC-MS: tR = 1.30 min, m/z (ES+) 706.48 (M+H)+, found 706.71. Example 34.
Figure imgf000314_0001
[0780] Compound 1.19 can be prepared by amide coupling of tetrapeptide with L- phenylalaninol. Example 35.
Figure imgf000314_0002
[0781] Compound 1.17 can be prepared by amide coupling of tetrapeptide with L- phenylalaninol. Example 36. General procedure to synthesize cyclic carbamate auristatins
Figure imgf000314_0003
[0782] Auristatin (1 equiv) was dissolved in DMF (0.3 M final concentration). DIPEA (5 equiv) and CDI (4 equiv) were added successively, and the reaction was stirred for 2 h. Upon reaction completion, a solution of LiOH was added to hydrolyze any undesired carbonate formation. The organic lay was separated, and the solvent was removed in vacuo. The crude mixture was purified by preparative HPLC. HPLC fractions were frozen and dried by lyophilization.
Figure imgf000314_0004
[0783] Compound 1.50. Analytical UPLC-MS: tR = 1.67 min, m/z (ES+) 732.45 (M+H)+, found 732.99. Example 37.
Figure imgf000315_0001
[0784] Compound 1.53. Analytical UPLC-MS: tR = 2.04 min, m/z (ES+) 732.45 (M+H)+, found 732.90. Example 38.
Figure imgf000315_0002
[0785] Compound 1.54. Analytical UPLC-MS: tR = 2.23 min, m/z (ES+) 702.44 (M+H)+, found 702.52. Example 39.
Figure imgf000315_0003
[0786] Compound 1.55. Analytical UPLC-MS: tR = 2.04 min, m/z (ES+) 785.43 (M+H)+, found 785.48. Example 40.
Figure imgf000315_0004
[0787] Compound 1.46. Analytical UPLC-MS: tR = 1.57 min, m/z (ES+) 718.44 (M+H)+, found 718.84. Example 41.
Figure imgf000315_0005
[0788] Compound 1.47. Analytical UPLC-MS: tR = 1.58 min, m/z (ES+) 732.45 (M+H)+, found 732.99. Example 42.
Figure imgf000316_0001
[0789] Compound 1.48. Analytical UPLC-MS: tR = 1.70 min, m/z (ES+) 732.45 (M+H)+, found 732.73. Example 43.
Figure imgf000316_0002
[0790] Compound 1.60. Analytical UPLC-MS: tR = 1.78 min, m/z (ES+) 760.49 (M+H)+, found 760.85. Example 44.
Figure imgf000316_0003
[0791] Compound 1.51. Analytical UPLC-MS: tR = 1.70 min, m/z (ES+) 732.45 (M+H)+, found 732.73. Example 45.
Figure imgf000316_0004
[0792] Compound 1.52. Analytical UPLC-MS: tR = 1.61 min, m/z (ES+) 732.45 (M+H)+, found 732.55. Example 46.
Figure imgf000317_0001
[0793] Compound 1.61 was prepared by amide coupling of tetrapeptide with L- phenylalaninol.. Analytical UPLC-MS (Method 1): tR = 1.25 min, m/z (ES+) 733.48 (M+H)+, found 733.78. Example 47.
Figure imgf000317_0002
[0794] Compound 1.28 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS (Method 1): tR = 1.24 min, m/z (ES+) 768.45 (M+H)+, found 768.60. Example 48.
Figure imgf000317_0003
[0795] Compound 1.62 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS (Method 1): tR = 1.20 min, m/z (ES+) 752.46 (M+H)+, found 752.19. Example 49.
Figure imgf000317_0004
[0796] Compoud 1.41 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS (Method 1): tR = 1.21 min, m/z (ES+) 718.47 (M+H)+, found 718.10. Example 50.
Figure imgf000318_0001
[0797] Compound 1.64 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS (Method 1): tR = 1.36 min, m/z (ES+) 769.45 (M+H)+, found 769.20. Example 51.
Figure imgf000318_0002
[0798] Compound 1.65 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS (Method 1): tR = 1.21 min, m/z (ES+) 749.47 (M+H)+, found 749.27. Example 52.
Figure imgf000318_0003
[0799] Compound 1.66 was prepared by amide coupling of tetrapeptide with L- phenylalaninol. Analytical UPLC-MS (Method 1): tR = 1.09 min, m/z (ES+) 727.43 (M+H)+, found 727.41. Example 53.
Figure imgf000319_0001
[0800] Compound 1.67 was prepared by amide coupling of tetrapeptide with 2-amino-3- (1H-1,2,3-triazol-1-yl)propan-1-ol.. Analytical UPLC-MS (Method 1): tR = 1.04 min, m/z (ES+) 711.47 (M+H)+, found 711.19. Example 54.
Figure imgf000319_0002
[0801] Compound 1.68 was prepared by amide coupling of tetrapeptide with 3-amino-4- phenylbutan-1-ol. Analytical UPLC-MS (Method 1): tR = 1.28 min, m/z (ES+) 734.50 (M+H)+, found 734.25. Example 55.
Figure imgf000319_0003
[0802] Compound 1.69 was prepared by amide coupling of tetrapeptide with 2-phenyl-1- (thiophen-2-yl)ethan-1-amine. Analytical UPLC-MS (Method 1): tR = 1.53 min, m/z (ES+) 772.46 (M+H)+, found 772.19. Example 56.
Figure imgf000319_0004
[0803] Compound 1.70 was prepared by amide coupling of tetrapeptide with 1-(oxazol-2- yl)-2-phenylethan-1-amine. Analytical UPLC-MS (Method 1): tR = 1.39 min, m/z (ES+) 757.48 (M+H)+, found 757.24. Example 57.
Figure imgf000320_0001
[0804] Compound 1.71 was prepared by amide coupling of tetrapeptide with (2R,3S)-3- amino-4-phenylbutane-1,2-diol. Analytical UPLC-MS (Method 1): tR = 1.18 min, m/z (ES+) 750.49 (M+H)+, found 750.20. Comparative Example A.
Figure imgf000320_0002
[0805] Comparative Example A was prepared by amide coupling of tetrapeptide with L- phenylalanine.. Analytical UPLC-MS (Method 1): tR = 1.34 min, m/z (ES+) 720.45 (M+H)+, found 720.38. Comparative Example B.
Figure imgf000320_0003
[0806] Comparative Example B was prepared using method A.Analytical UPLC-MS (Method 1): tR = 1.79 min, m/z (ES+) 1318.73 (M+H)+, found 1319.21. Comparative Example C.
Figure imgf000321_0001
[0807] Comparative Example C was prepared in a similar fashion to Example 36.Analytical UPLC-MS (Method 1): tR = 1.73 min, m/z (ES+) 746.43 (M+H)+, found 746.76. General procedures for solution phase synthesis of auristatins Example 58. General procedure for synthesis of dipeptide carbamate linkers (Method A) Step 1. Synthesis of MC-VC-PAB-OPFP
Figure imgf000321_0002
[0808] A 20 mL vial equipped with stir bar was charged with MC-VC-PABA (300 mg, 0.52 mmol), PFP carbonate (413mg, 1.04 mmol), DMF (5 mL), and DIPEA (137uL, 0.78 mmol). The mixture was stirred at RT for 3 hours. The solvent was removed in vacuo and redissolved in 20% piperidine in DMF (5 mL). The reaction was stirred for 1 hour. The solvent was removed in vacuo and was purified by Biotage reverse phase flash column chromatography with acetonitrile + 0.05% TFA and water + 0.05% TFA gradient up to 95% acetonitrile. The product fractions were lyophilized to afford 177 mg (43% yield). Analytical UPLC-MS: tR = 2.05 min, m/z (ES+) 783.27 (M+H)+, found 783.42.
Step 2. Drug-Linker formation
Figure imgf000322_0001
[0809] A 20 mL vial equipped with stir bar was charged with the compound of Example 12 (70 mg, 0.1 mmol), MC-VC-PAB-OPFP (78 mg, 0.1 mmol), DMF (5 mL), and DIPEA (26 uL, 0.15 mmol). The mixture was stirred at RT overnight. The solvent was removed in vacuo and was purified by preparative HPLC. The product fractions were lyophilized to afford 80.7 mg (62 % yield) of compound 2.2. Analytical UPLC-MS: tR = 1.82 min, m/z (ES+) 1304.75 (M+H)+, found 1305.54.
Example 59. General procedure for synthesis of (D)Leu-Ala-Glu tripeptide carbamate drug-linkers (Method B)
Figure imgf000323_0001
[0810] This is a modified version of a previously reported procedure. See WO 2021/055865. [0811] A 4 mL vial equipped with stir bar was charged with the compound from Example 12 (100 mg, 0.14 mmol), MC-(D)-Leu-Ala-Glu(OtBu)-PABA-OpNP (114 mg, 0.14 mmol), DMF (5 mL), DIPEA (51 uL, 0.28 mmol), and HOBt (37 mg, 0.28 mmol). The mixture was stirred at RT overnight. The solvent was removed in vacuo. [0812] The crude mixture was dissolved in propionitrile (3 mL), and H3PO4 (3 mL) was slowly added to the reaction mixture at RT. The reaction mixture was stirred for 2 h and priopionitrile (6 mL) was added to the mixture. The organic layer was separated, and the reaction was concentrated and purified by HPLC. The product fractions were lyophilized to afford 54 mg (26% yield) of compound 2.6. [0813] Analytical UPLC-MS: tR = 1.71 min, m/z (ES+) 1319.71 (M+H)+, found 1320.06. Example 60. General procedure for synthesis of quaternary linkers (Method C) Step 1. Synthesis of MC-VC-PAB-Cl
Figure imgf000324_0001
[0814] A 20 mL vial equipped with stir bar was charged with solution of MC-Val-Cit- PAB-OH (200 mg, 349.25 umol) in N-methyl-2-pyrrolidone (NMP, 3 mL) and then cooled to 0°C. A solution of SOCl2 (70.64 mg, 593.73 umol) in NMP (0.5 mL) was added dropwise. The mixture was stirred at 20°C for 30 min. TLC (ethyl acetate: methanol = 3: 1, Rf = 0.5) showed the reaction was completed. The mixture was poured into ice water and filtered, washed with acetonitrile and ethyl acetate, dried in high vacuum to give MC-Val-Cit-PAB-Cl (100 mg, yield 48.4%). Analytical UPLC-MS: tR = 2.05 min, m/z (ES+) 591.27 (M+H)+, found 591.42. 1H NMR: (400MHz, DMSO-d6) δ = 10.16 – 9.89 (m, 1H), 8.08 (br d, J=7.4 Hz, 1H), 7.79 (br d, J=8.6 Hz, 1H), 7.60 (br d, J=8.5 Hz, 2H), 7.36 (d, J=8.5 Hz, 2H), 7.00 (s, 2H), 5.96 (br t, J=5.4 Hz, 1H), 5.52 – 5.20 (m, 2H), 4.71 (s, 2H), 4.45 – 4.31 (m, 1H), 4.19 (br t, J=7.6 Hz, 1H), 3.45 – 3.34 (m, 2H), 3.09 – 2.85 (m, 2H), 2.14 (tq, J=7.2, 14.5 Hz, 2H), 2.03 – 1.85 (m, 1H), 1.75 – 1.55 (m, 2H), 1.54 – 1.27 (m, 6H), 1.26 – 1.10 (m, 2H), 0.83 (br dd, J=6.8, 12.9 Hz, 6H). Step 2. Drug-Linker formation
Figure imgf000324_0002
[0815] A 4 mL vial equipped with stir bar was charged with the compound of Example 8 (3.3 mg, 0.004 mmol), mc-VC-PAB-Cl (4.8 mg, 0.008 mmol), DMA (0.5 mL), and NaI (1.2 mg, 0.008 mmol). The mixture was stirred at 70⁰ C for 4 hours. The reaction was purified by preparative HPLC. The product fractions were lyophilized to afford 3.9 mg (71% yield) of the title compound (compound 2.1). Analytical UPLC-MS : tR = 1.51 min, m/z (ES+) 1275.62 (M)+, found 1275.46. Example 61.
Figure imgf000325_0001
[0816] Compound 2.2 was synthesized using method A. 62% yield. Analytical UPLC- MS: tR = 1.82 min, m/z (ES+) 1304.75 (M+H)+, found 1305.54. Example 62.
Figure imgf000325_0002
[0817] Compound 2.9 was synthesized using method A. 43% yield. Analytical UPLC- MS: tR = 1.72 min, m/z (ES+) 1290.73 (M+H)+, found 1291.59. Example 63.
Figure imgf000325_0003
[0818] Compound 2.10 was synthesized using method A. 52% yield. Analytical UPLC- MS: tR = 1.74 min, m/z (ES+) 1304.75 (M+H)+, found 1305.28. Example 64.
Figure imgf000326_0001
[0819] Compound 2.11 was synthesized using method A. 64% yield. Analytical UPLC- MS: tR = 1.77 min, m/z (ES+) 1304.75 (M+H)+, found 1304.61. Example 65.
Figure imgf000326_0002
[0820] Compound 2.12 was synthesized using method A. 15% yield. Analytical UPLC- MS: tR = 1.92 min, m/z (ES+) 1332.78 (M+H)+, found 1333.51. Example 66.
Figure imgf000326_0003
[0821] Compound 2.13 was synthesized using method A. 57% yield. Analytical UPLC- MS: tR = 1.68 min, m/z (ES+) 1304.75 (M+H)+, found 1305.43. Example 67.
Figure imgf000327_0001
[0822] Compound 2.14 was synthesized using method A. 47% yield. Analytical UPLC- MS: tR = 1.72 min, m/z (ES+) 1318.77 (M+H)+, found 1319.31. Example 68.
Figure imgf000327_0002
[0823] Compound 2.19 was synthesized using method A. 80% yield. Analytical UPLC- MS: tR = 1.75 min, m/z (ES+) 1322.74 (M+H)+, found 1323.30. Example 69.
Figure imgf000327_0003
[0824] Compound 2.20 was synthesized using method A. 22% yield. Analytical UPLC- MS: tR = 1.67 min, m/z (ES+) 1291.58 (M+H)+, found 1291.42. Example 70.
Figure imgf000328_0001
[0825] Compound 2.3 was synthesized using method A. Analytical UPLC-MS: tR = 1.71 min, m/z (ES+) 1305.60 (M+H)+, found 1304.91. Example 71.
Figure imgf000328_0002
[0826] Compound 2.29 was synthesized using method A. Example 72.
Figure imgf000328_0003
[0827] Compound 2.21 was synthesized using method A. Example 73.
Figure imgf000328_0004
[0828] Compound 2.22 was synthesized using method A. 27% yield. Analytical UPLC- MS: tR = 1.87 min, m/z (ES+) 1346.80 (M+H)+, found 1347.50. Example 74.
Figure imgf000329_0001
[0829] Compound 2.14 was synthesized using method A. Analytical UPLC-MS: tR = 1.57 min, m/z (ES+) 1332.77 (M+H)+, found 1332.81. Example 75.
Figure imgf000329_0002
[0830] Compound 2.4 was synthesized using method A. Analytical UPLC-MS: tR = 1.64 min, m/z (ES+) 1248.69 (M+H)+, found 1249.42. Example 76.
Figure imgf000329_0003
[0831] Compound 2.5 was synthesized using method A. Analytical UPLC-MS: tR = 1.85 min, m/z (ES+) 1277.71 (M+H)+, found 1278.21. Example 77.
Figure imgf000330_0001
[0832] Compound 2.6 was synthesized using method B. Analytical UPLC-MS: tR = 1.69 min, m/z (ES+) 1319.71 (M+H)+, found 1319.75. Example 78.
Figure imgf000330_0002
[0833] Compound 2.16 was synthesized using method B. Analytical UPLC-MS: tR = 1.71 min, m/z (ES+) 1289.70 (M+H)+, found 1289.83. Example 79.
Figure imgf000330_0003
[0834] Compound 2.17 was synthesized using method B. Analytical UPLC-MS: tR = 1.75 min, m/z (ES+) 1372.69 (M+H)+, found 1372.75. Example 80.
Figure imgf000330_0004
[0835] Compound 2.18 was synthesized using method B. Analytical UPLC-MS: tR = 1.81 min, m/z (ES+) 1386.70 (M+H)+, found 1386.73. Example 81.
Figure imgf000331_0001
[0836] Compound 2.23 was synthesized using method C. Analytical UPLC-MS: tR = 1.52 min, m/z (ES+) 1288.79 (M)+, found 1288.88. Example 82.
Figure imgf000331_0002
[0837] Compound 2.24 was synthesized using method C. Analytical UPLC-MS: tR = 1.39 min, m/z (ES+) 1288.79 (M)+, found 1288.82. Example 83.
Figure imgf000331_0003
[0838] Compound 2.25 was synthesized using method C. Analytical UPLC-MS: tR = 1.51 min, m/z (ES+) 1274.78 (M)+, found 1274.88. Example 84.
Figure imgf000332_0001
[0839] Compound 2.26 was synthesized using method C. Analytical UPLC-MS: tR = 1.60 min, m/z (ES+) 1289.74 (M)+, found 1289.92. Example 85.
Figure imgf000332_0002
[0840] Modified – compound 2.7 synthesized according to a known procedure (Burke, P. J. et al. Mol. Cancer Ther. 2017, 16, 116-123). [0841] Analytical UPLC-MS: tR = 1.68 min, m/z (ES+) 1241.58 (M+H)+, found 1241.25. Example 86. Measurement of LogD [0842] The LogD (distribution coefficient) of the compounds was measured using a miniaturized 1-octanol/pH 7.4 buffer shake flask method followed by LC/MS/MS analysis. Values were determined by measuring the compound partitioned in the organic and buffered layers. Results are shown in Table 4. Example 87. In vitro cytotoxicity [0843] The cytotoxicity of free drugs and drug conjugates were measured by a cell proliferation assay employing the protocol described in Promega Corp. Technical Bulletin TB288; and Mendoza et al., 2002, Cancer Res. 62:5485-5488), the methods of which are specifically incorporated by reference herein. Briefly, an aliquot of 40 µl of cell culture containing about 400 cells in medium is deposited in each well of a 384-well, opaque-walled plate. A 10 µL aliquot of free drug or drug conjugate is added to the experimental wells and incubated for 96 h and are then equilibrated to room temperature for approximately 30 minutes whereupon a volume of CellTiter-GloTM reagent equal to the volume of cell culture medium present in each well is added. The contents are mixed for 2 minutes on an orbital shaker to induce cell lysis and the plate is incubated at room temperature for 10 minutes to stabilize the luminescence signal for recordation. Results are shown in Table 4. Table 4A. Auristatin free drug LogD values and in vitro IC50 (nM) values on cancer cell lines.
Figure imgf000333_0001
Figure imgf000334_0001
Table 4B. Auristatin free drug in vitro IC50 (nM) values on cancer cell lines.
Figure imgf000334_0002
Example 88. Conjugation of Drug-Linker compounds to antibodies to form Ligand- Drug Conjugate compounds [0844] Antibodies were partially reduced using the appropriate equivalents of TCEP according to the procedure, which is specifically incorporated by reference herein, of US 2005/0238649. Briefly, the antibody in phosphate buffered saline with 2 mM EDTA, pH 7.4, was treated with 2.1 eq. TCEP and then incubated at 37⁰ C for about 45 minutes. The thiol/Ab value was checked by reacting the reduced antibody with MC-VC-MMAE and using hydrophobic interaction chromatography to determine the loading. [0845] The auristatin drug linker compounds were conjugated to the partially reduced antibody using the method, which is specifically incorporated by reference herein, of US 2005/0238649. Briefly, Drug-Linker compound (50% excess) in DMSO, was added to the reduced antibody in PBS with EDTA along with additional DMSO for a total reaction co- solvent of 10-20%. After 30 minutes at ambient temperature, an excess of QuadraSil MPTM was added to the mixture to quench all unreacted maleimide groups. The resulting Ligand- Drug Conjugate compound was then purified, and buffer exchanged by desalting using Sephadex G25 resin into pH 6.5 histidine buffer and kept at -80⁰ C until further use. The protein concentration of the resulting ADC composition was determined at 280 nm. The drug-antibody ratio (DAR) was confirmed by comparing predicted and observed changes in the molecular weights of heavy and light chains using PLRP-MS analysis and confirming absence of underloaded species. Example 89. In vivo cytotoxicity of Ligand-Drug Conjugate compounds [0846] Cancer cells were implanted into mice. Upon tumor engraftment, mice were randomized to study groups (n = 5) once the average tumor volume reached approximately 100 mm3. ADC prepared from reduced antibody and compound was administered via an intraperitoneal or intravenous injection. Tumor volumes are calculated using the formula (0.5xLxW2) where L and W are the longer and shorter of two bidirectional measurements. Complete response (CR) is defined here as absence of measurable mass at tumor site during an experiment. Results are showin in FIGs. 1 to 5 and in Table 5 for Ligand-Drug Conjugate compounds with an average drug loading of 4 Drug-Linker moieties per antibody. [0847] FIG. 1 shows the efficacy of a 6mg/kg dose of a variety of Ag1 ADCs as measured in the A2058 melanoma xenograft model. The data show that Ag1 ADCs comprising hydrophilic auristatin Drug Units have efficacy comparable to ADCs comprising MMAE. [0848] FIG. 2 shows the efficacy of a 3mg/kg dose of a variety of h2A2 ADCs as measured in the Detroit 562-39 pharyngeal xenograft model. The data show that h2A2 ADCs comprising hydrophilic auristatin Drug Units have efficacy comparable to ADCs comprising MMAE. [0849] FIG. 3 shows the efficacy of a 3 mg/kg dose of a variety of cAC10 ADCs as measured in the Karpas/KarpasBVR admixed Hodgkin lymphoma xenograft model. The data show that cAC10 ADCs with hydrophilic auristatin Drug Units have bystander activity between that of MC-VC-MMAE and MC-VC-MMAF. [0850] FIG. 4 shows the efficacy of a 1 mg/kg dose of a variety of cAC10 ADCs in the Karpas Hodgkin lymphoma xenograft model. The data show that cAC10 ADCs comprising hydrophilic auristatin Drug Units have efficacy comparable to ADCs comprising MMAE. [0851] FIG. 5 shows the efficacy of a 1 mg/kg dose of a variety of cAC10 ADCs in the Karpas Hodgkin xenograft model. The data show that cAC10 ADCs comprising hydrophilic auristatin Drug Units have efficacy comparable to ADCs comprising MMAE. Example 90. Toxicity Determinations of Ligand-Drug Conjugate compounds. [0852] In vivo rat safety studies were done in naive female Sprague Dawley rats (Envigo). Studies had 3 animals/group/timepoint and included a vehicle control group (1X PBS pH 7.4). Animals were administered a single dose of 15 or 80 mg/kg of an h00 ADC (DAR = 4) via intravenous injection. Blood was drawn at days 5 and day 8. Blood was sampled under isoflurane anesthesia via the jugular vein for periodic hematology analysis on the Sysmex XT-2000iV. At necropsy, blood was collected from the caudal vena cava for hematology and clinical chemistry panels. Clinical chemistry was analyzed on a Beckman Coulter AU680. Results are shown in FIGs. 6 to 9. [0853] FIG. 6 demonstrates that neutrophil counts are higher at on Day 5 and recovery of neutrophil counts on Day 8 are higher after administering Ligand-Drug Conjugate compounds comprising hydrophilic auristatin Drug Units when compared to MMAE containing conjugates. [0854] FIG. 7 demonstrates that recovery of reticulocytes is greatly improved after administering Ligand-Drug Conjugate compounds comprising hydrophilic auristatin Drug Units when compared to MMAE containing conjugates. [0855] FIG. 8 shows that administering Ligand-Drug Conjugate compounds with hydrophilic auristatin Drug Units does not impact the platelet count as heavily as administering an MMAF containing conjugate. Recovery of platelets is also better after administering Ligand-Drug Conjugate compounds comprising hydrophilic auristatin Drug Units when compared to MMAE and MMAF containing conjugates. [0856] FIG. 9 shows that aspartate transaminease (AST) levels indicating liver damage are lower 8 days after administering 80 mg/kg of Ligand-Drug Conjugate compounds comprising hydrophilic auristatin Drug Units when compared to after administering 15 mg/kg of an MMAF containing conjugates. The AST levels 8 days following administration are comparable for an 80 mg/kg dose of some Ligand-Drug Conjugate compounds comprising hydrophilic auristatin Drug Units when compared to a 15 mg/kg dose of an MMAE conjugate. Table 5A. In vitro IC50 (ng/mL) values of auristatin anti-CD30 ADCs on CD30- expressing cell lines using cAC10 ADCs with an average drug loading of about 4 of selected Drug-Linker compounds.
Figure imgf000337_0001
Table 5B. In vitro IC50 (ng/mL) values of auristatin anti-CD30 ADCs on CD30- expressing cell lines using cAC10 ADCs with an average drug loading of about 4 of selected Drug-Linker compounds.
Figure imgf000338_0001
Table 5C. In vitro IC50 (ng/mL) values of auristatin anti-CD30 ADCs on CD30- expressing cell lines using cAC10 ADCs with an average drug loading of about 4 of selected Drug-Linker compounds.
Figure imgf000338_0002
Table 5D. In vitro IC50 (ng/mL) values and tolerability of auristatin anti-CD30 ADCs on CD30-expressing cell lines using cAC10 ADCs with an average drug loading of about 4 of selected Drug-Linker compounds.
Figure imgf000338_0003
Example 91. Comparison of compound tolerability [0857] Tolerability of an ADC comprising the compound of Example 8 of the present application was compared to tolerability of ADCs comprising the known compounds MMAE and MMAF. Without being bound by theory, the improvements in tolerability are believed to be related to reduced toxicities in the bone marrow and in the liver that are a result of the OH moieties on the compound of Example 8. See Table 6 below. Table 6. Tolerability comparison of compound 1.1 to MMAE and MMAF
Figure imgf000339_0001
^ Average cytotoxicity of DEL, Karpas299, and L540cy cell lines * anti-CD30 ADCs ** Dosed in Sprague-Dawley Rats Example 92. In vitro quantitative flow cytometry of cancer cell lines [0858] Cancer cells were counted and 100,000-200,000 cells were plated in 100 µL FACS buffer in 96-well U-bottom plates (Falcon). Cells were incubated with 10 ug/mL of non-binding and targeted (hCR011) human IgG for one hour at 4°C. Cells were washed 3x before anti-IgG FITC secondary antibody and calibration beads from Human IgG Calibrator Kit (BioCytex Ref#CP101) were added for 30 minutes at 4°C. Cells were washed 2x and run on an Attune cytometer. Data was analyzed using FlowJo software (BD). Target antigen (gpNMB) copy number was determined per manufacturer’s instructions; briefly, the MFI values of calibration beads were used to determine the antibody binding capacity and the specific antibody binding capacity (SABC) was determined by subtracting the non-binding IgG MFI from the targeted (hCR011) MFI. The SABC numbers for hCR011 (i.e. gpNMB copy number) are summarized in Table 7. Table 7. gpNMB (hCR011) copy numbers for a panel of cancer cell lines
Figure imgf000339_0002
Figure imgf000340_0001
Example 93: In vitro cytotoxicity of Auristatin ADCs in a panel of cancer cell lines [0859] Cancer cells were counted and plated in 40 µL complete growth media in 384- well, white-walled tissue culture treated plates (Corning). Cell plates were incubated at 37°C and with 5% CO2 overnight to allow the cells to equilibrate. Stock solutions containing ADCs or free drugs were serially diluted in RPMI-1640 + 20% fetal bovine serum (FBS). 10 µL of each concentration were then added to each cell plate in duplicate. Cells were then incubated at 37°C and with 5% CO2 for 96 hours, upon which, the cell plates were removed from the incubator and allowed to cool to room temperature for 30 minutes prior to analysis. CellTiter- Glo® luminescent assay reagent (Promega Corporation, Madison, WI) was prepared according to Promega’s protocol. 10 µL of CellTiter-Glo® were added to assay plates using a Formulatrix Tempest liquid handler (Formulatrix) and the plates were protected from light for 30 minutes at room temperature. The luminescence of the samples was measured using an EnVision Multimode plate reader (Perkin Elmer, Waltham, MA). Raw data were analyzed in Graphpad Prism (San Diego, CA) using a nonlinear, 4-parameter curve fit model [Y=Bottom + (Top-Bottom)/(1+10^((LogEC50-X)*HillSlope))]. Results are reported as IC50 values, which are defined as the concentration of ADC or free drug required to reduce cell viability to 50%. The cytotoxic activity of auristatin free drugs and ADCs on cancer cell lines is summarized in Tables 8 and 9. Table 8: Cytotoxicity of auristatin ADCs on a panel of cancer cell lines *Cancer cell lines with > 2000 surface copy number of target antigen (determined by quantitative flow cytometry) were considered positive (“+”).
Figure imgf000340_0002
Figure imgf000341_0001
Table 9: Cytotoxicity of auristatin free drugs and ADCs on a panel of cancer cell lines *Cancer cell lines with > 2000 surface copy number of target antigen (determined by quantitative flow cytometry) were considered positive (“+”).
Figure imgf000341_0002
Example 94: In vivo antitumor activity of Auristatin ADCs in WM2664 and SKMEL5 xenograft tumor models [0860] Cancer cells were implanted into nude mice. Upon tumor engraftment, mice were randomized to study groups (n = 5) and when tumor volumes reached 100 mm3, the mice were dosed with ADCs by intravenous injection at the indicated dose Q1Wx3 (3 weekly doses) and tumor volumes were monitored twice weekly. Tumor volumes are calculated using the formula (0.5xLxW2) where L and W are the longer and shorter of two bidirectional measurements. Complete response (CR) is defined here as absence of measurable mass at tumor site during an experiment. Results are shown in Figures 10-11 for Ligand-Drug Conjugate compounds with an average drug loading of 4 Drug-Linker moieties per antibody. [0861] FIG. 10 shows the efficacy of a variety of hCR011 ADCs and a non-binding control ADC as measured in the WM2664 melanoma xenograft model. The data show that hCR011 ADCs comprising hydrophilic auristatin Ex. 60 dosed at 3 mg/kg (3 weekly doses) have efficacy comparable to ADCs comprising MMAE. When hCR011-Ex. 60 ADCs are dosed at 9 mg/kg (3 weekly doses), there are 4/5 complete responses. [0862] FIG. 11 shows the efficacy of a variety of hCR011 ADCs and non-binding control ADCs as measured in the SKMEL5 melanoma xenograft model. The data show that hCR011 ADCs comprising hydrophilic auristatin Ex. 60 dosed at 9 mg/kg (3 weekly doses) have efficacy comparable to ADCs comprising MMAE dosed at 3 mg/kg (3 weekly doses). Example 95: Antitumor activity of Auristatin ADCs in patient-derived xenograft (PDX) models of melanoma and non-small cell lung cancer (NSCLC) [0863] Cancer cells were implanted into Nude (Nude-Foxn1nu) female mice. When tumors reached an average tumor volume of 150-300 mm³ animals were matched by tumor volume into treatment or control groups and dosed with ADCs by intravenous injection at the indicated dose Q1Wx3 (3 weekly doses) and tumor volumes were monitored twice weekly. The study endpoint was when the mean tumor volume of the control group (uncensored) reached 1500 mm³. Complete response (CR) is defined here as absence of measurable mass at tumor site during an experiment. Results are shown in Figures 12-15 for Ligand-Drug Conjugate compounds with an average drug loading of 4 Drug-Linker moieties per antibody. Ag2 refers to an antibody targeting a ubiquitous and readily internalizable antigen on cancer cells. [0864] FIG. 12 shows the efficacy of non-binding, Ag2, and hCR011 ADCs as measured in the PDX_1 melanoma xenograft model. The data show that hCR011 ADCs comprising hydrophilic auristatin Ex. 60 (compound 3.1 wherein L is hCR011) dosed at 3 mg/kg have efficacy comparable to ADCs comprising MMAE dosed at 3 mg/kg. Ag2 and hCR011 ADCs with Ex. 60 (compound 3.1 wherein L is hCR011) dosed at 9 mg/kg elicited more robust antitumor activity. [0865] FIG. 13 shows the efficacy of non-binding, Ag2, and hCR011 ADCs as measured in the PDX_4 melanoma xenograft model. The data show that hCR011 ADCs comprising hydrophilic auristatin Ex. 60 (compound 3.1 wherein L is hCR011) dosed at 3 mg/kg have efficacy comparable to ADCs comprising MMAE dosed at 3 mg/kg. Ag2 and hCR011 ADCs with Ex. 60 (compound 3.1 wherein L is Ag2 or hCR011, respectively) dosed at 9 mg/kg elicited more robust antitumor activity, with hCR011-Ex. 60 ADCs leading to 2/5 complete responses. [0866] FIG. 14 shows the efficacy of non-binding, Ag2, and hCR011 ADCs as measured in the PDX_3 NSCLC xenograft model. The data show that Ag2 and hCR011 ADCs comprising hydrophilic auristatin Ex. 60 (compound 3.1 wherein L is Ag2 or hCR011, respectively) dosed at 3 and/or 9 mg/kg have efficacy comparable to ADCs comprising MMAE dosed at 3 mg/kg. [0867] FIG. 15 shows the efficacy of non-binding, Ag2, and hCR011 ADCs as measured in the PDX_2 NSCLC xenograft model. The data show that Ag2 and hCR011 ADCs comprising hydrophilic auristatin Ex. 60 (compound 3.1 wherein L is Ag2 or hCR011, respectively) dosed as 9 mg/kg have comparable efficacy to ADCs comprising MMAE dosed at 3 mg/kg. Example 96: Efficacy comparison of in vivo tumor models [0868] Average Slope or AUC.3 was used to compare the anti-tumor activity of 6 different xenograft models. Tumor growth was assessed by the metric area under the curve (AUC), “AUC.3”, based on Guo et al.’s best practices for reporting pre-clinical data, which
Figure imgf000343_0001
reflects area under a continuous growth curve and accounts for time on study (Guo S, Jiang X, Mao B, et al. The design, analysis, and application of mouse clinical trials in oncology drug development. BMC Cancer 2019;19:718). [0869] The data (see FIG 16) show that hCR011 ADCs comprising hydrophilic auristatin Ex. 60 (compound 3.1 wherein L is hCR011) dosed at 3 mg/kg and 9 mg/kg have comparable and enhanced efficacy, respectively, to ADCs comprising MC-VC-MMAE dosed at 3 mg/kg. Example 97. Toxicity Determinations of Ligand-Drug Conjugate compounds [0870] In vivo safety studies were done in naive cynomolgus monkeys. Studies had 1 or 2 animals/group/timepoint of hCR011-MC-VC-MMAE (DAR = 4) or hCR011-Example 60 (DAR = 4). Animals were administered four weekly doses of 3, 5, or 10 mg/kg of ADC via intravenous (slow bolus) injection. Baseline measurements for hematology and clinical chemistry parameters were taken from blood drawn at one or two time points prior to dosing, and post-dose timepoints were collected at day 8, and also on days 15 and 29 (hematology only). Results are shown in FIGs. 17 to 20. [0871] FIG. 17 demonstrates that neutrophil counts post-administration of hydrophilic auristatin conjugate hCR011-Example 60 at 5 and 10 mg/kg were maintained at baseline levels, whereas conjugate hCR011-MC-VC-MMAE at 3 mg/kg shows a decrease relative to baseline on days 8, 15, and 29. [0872] FIG. 18 demonstrates that loss of reticulocytes is greatly improved after administering hydrophilic auristatin conjugate hCR011-Example 60 at 5 and 10 mg/kg compared to conjugate hCR011-MC-VC-MMAE at 3 mg/kg. [0873] FIG. 19 shows that administering hydrophilic auristatin conjugate hCR011- Example 60 does not significantly impact platelet counts at higher dose-levels of 5 and 10 mg/kg compared to conjugate hCR011-MC-VC-MMAE at 3 mg/kg. [0874] FIG. 20 shows that administering hydrophilic auristatin conjugate hCR011- Example 60 does not significantly impact AST levels at higher dose-levels of 5 and 10 mg/kg compared to conjugate hCR011-MC-VC-MMAE at 3 mg/kg. Example 98. Toxicity Determinations of Ligand-Drug Conjugate compounds [0875] In vivo toxicology studies were done in naive cynomolgus monkeys. Studies had 2 animals/group/timepoint of hCR011-MC-VC-MMAE (DAR = 4) or hCR011-Example 60 (DAR = 4). Animals were administered four weekly doses of 5 mg/kg of ADC via intravenous (slow bolus) injection. Baseline measurements for hematology parameters were collected and results are shown in FIG. 21. The 5 mg/kg dose of hCR011-MC-VC-MMAE was not tolerated and dosing could not be completed for both animals whereas animals treated with 5 mg/kg of hCR011-Example 60 completed the study as planned. [0876] FIG. 21 shows neutrophil counts from blood samples taken prior to dosing and post-dose on Day 8. Neutrophil counts post-administration of hydrophilic auristatin conjugate hCR011-Example 60 dosed at 5 mg/kg were maintained at baseline levels, whereas conjugate hCR011-MC-VC-MMAE at 5 mg/kg showed a decrease relative to baseline. [0877] While the foregoing written description of the compounds, uses, and methods described herein enables one of ordinary skill to make and use the compounds, uses, and methods described herein, those of ordinary skill will understand and appreciate the existence of variations, combinations, and equivalents of the specific embodiment, method, and examples herein. The compounds, uses, and methods provided herein should therefore not be limited by the above-described embodiments, methods, or examples, but rather encompasses all embodiments and methods within the scope and spirit of the compounds, uses, and methods provided herein. [0878] All references disclosed herein are incorporated by reference in their entirety. [0879] Unless otherwise indicated, all sequences and SEQ IDs referenced in the application correspond to the appropriately numbered sequence in the table below. [0880] The Table of Sequences below provides exemplary antibody sequences consistent with the present disclosure. In this table, all targets correspond to human orthologs unless otherwise specified.
Figure imgf000345_0001
Figure imgf000346_0001
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Figure imgf000388_0001

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula (I):
Figure imgf000389_0001
or a salt thereof, wherein
Figure imgf000389_0002
Xa and Xb are taken together with the carbon atom to which they are attached to form
Figure imgf000389_0003
, wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups; R1, R2, R3, R4, Ra, Rb, R5, and R10 are each independently H or C1-C4 alkyl; X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; and q is 0 or 1, wherein when X is H, at least two of R7, R8, R9, and R11 comprise an OH moiety.
2. A compound of Formula (II):
Figure imgf000390_0001
or a salt thereof, wherein R1, R3, and R4 are independently H or C1-C4 alkyl; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, or 2; and q is 0 or 1.
3. The compound of claim 1 or 2, wherein q is 0.
4. The compound of claim 1 or 2, wherein q is 1.
5. The compound of claim 1, or a salt thereof, wherein X is OH.
6. The compound of claim 1, or a salt thereof, wherein X is -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra.
7. The compound of any one of claims 1 or 3-6, or a salt thereof, wherein Xb is -NR1R2; and
Figure imgf000390_0002
.
8. The compound of any one of claims 1-7, or a salt thereof, wherein R3 is H.
9. The compound of any one of claims 1-8, or a salt thereof, wherein R4 is H.
10. The compound of any one of claims 1-9, or a salt thereof, wherein n is 0 or 1.
11. The compound of any one of claims 1 or 3-6, or a salt thereof, wherein Xa and Xb are taken together with the carbon atom to which they are attached to form
Figure imgf000391_0001
, wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups.
12. The compound of any one of claims 1 or 3-11, wherein m is 1 or 2.
13. The compound of any one of claims 1-10, or a salt thereof, wherein R1 is H.
14. The compound of any one of claims 1-10, or a salt thereof, wherein R1 is C1-C4 alkyl.
15. The compound of any one of claims 1-10 or 14, or a salt thereof, wherein R1 is methyl.
16. The compound of any one of claims 1, 3-10, or 13-15, or a salt thereof, wherein R2 is methyl.
17. The compound of any one of claims 1-16, or a salt thereof, wherein R10 is H.
18. The compound of any one of claims 1-16, or a salt thereof, wherein R10 is methyl.
19. The compound of any one of claims 1-18, or a salt thereof, wherein R6 is unsubstituted C1-C4 alkyl.
20. The compound of any one of claims 1-19, or a salt thereof, wherein R6 is isopropyl.
21. The compound of any one of claims 1-18, or a salt thereof, wherein R6 is C1-C4 alkyl substituted with OH.
22. The compound of any one of claims 1-21, or a salt thereof, wherein R7 C1-C4 alkyl substituted with OH.
23. The compound of any one of claims 1-22, or a salt thereof, wherein R7 is -CH2OH.
24. The compound of any one of claims 1-21, or a salt thereof, wherein R7 is H.
25. The compound of any one of claims 1-21, or a salt thereof, wherein R7 is unsubstituted C1-C4 alkyl.
26. The compound of any one of claims 1-21 or 25, or a salt thereof, wherein R7 is methyl.
27. The compound of any one of claims 1-21, or a salt thereof, wherein R7 is 5-6 membered heteroaryl.
28. The compound of any one of claims 1-27, or a salt thereof, wherein R8 is H.
29. The compound of any one of claims 1-28, or a salt thereof, wherein R8 is OH.
30. The compound of any one of claims 1-29, or a salt thereof, wherein E is phenyl.
31. The compound of any one of claims 1-30, or a salt thereof, wherein E-R9 is ; and the wavy line indicates the point of attachment of E to the rest of the compound.
32. The compound of any one of claims 1-29, or a salt thereof, wherein E is 5-6 membered heteroaryl.
33. The compound of any one of claims 1-32, or a salt thereof, wherein R9 is H.
34. The compound of any one of claims 1-33, or a salt thereof, wherein R9 is OH.
35. The compound of claim 1, or a salt thereof, wherein
Figure imgf000393_0001
Xb is -NR1R2; R1 is H or methyl; R2 is methyl; X is OH; R3 and R4 are H; R6 is isopropyl; R7 is -CH2OH; R8 is H; E is phenyl; and R9 is H.
36. The compound of claim 1, wherein the compound is
Figure imgf000393_0002
or a salt thereof.
37. A Drug-Linker compound of the following formula: Q-D, or a salt thereof, wherein Q is a Linker Unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S*-RL-, (iv) Z'-A-S*-RL-Y-, (v) Z'-A-B(S*)-RL-, (vi) Z'-A-B(S*)-RL-Y-, (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-; Z' is a Stretcher Unit precursor; A is a bond or a Connector Unit; B is a Parallel Connector Unit; S* is a Partitioning Agent; RL is a Releasable Linker; W is an Amino Acid Unit; Y is a Spacer Unit; and D is a Drug Unit of Formula (I'):
Figure imgf000394_0001
wherein Xb is -NR2-# or -N+R1R5-#, wherein the # denotes the point of attachment to Q, and Xa is or
Figure imgf000394_0002
Xa and Xb are taken together with the carbon atom to which they are attached to form
Figure imgf000394_0003
, wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups, and the # denotes the point of attachment to Q; R1 and R5 are independently C1-C4 alkyl; X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R2, R3, R4, R10, Ra, and Rb are each independently H or C1-C4 alkyl; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1; and wherein when X is H, at least two of R7, R8, R9, and R11 comprise an OH moiety.
38. The Drug-Linker compound of claim 37, or a salt thereof, wherein the Linker Unit Q is of formula (i), (ii), (iii), (iv), (x), or (xi).
39. The Drug-Linker compound of claim 37, or a salt thereof, wherein the Linker Unit Q is of formula (v), (vi), (ix), or (xi).
40. The Drug-Linker compound of claim 37, or a salt thereof, wherein the Linker Unit Q is of formula (viii), (ix), (x), or (xi).
41. The Drug-Linker compound of any one of claims 37-40, or a salt thereof, wherein the Stretcher Unit Z' is
Figure imgf000395_0001
wherein R17 is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O-(C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3- C8 heterocyclo-, -C1-C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene- , -C1-C10 alkylene-C(=O)-, C1-C10 heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O- (C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8 heterocyclo)-C(=O)-, - (C3-C8 heterocyclo)-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-NH-, C1-C10 heteroalkylene- NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene- arylene-NH-, -arylene-C1-C10 alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, -(C3- C8 carbocyclo)-C1-C10 alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, -C3-C8 carbocyclo-S -, -O-(C1-C8 alkylene)-S -, -arylene-S-, -C1-C10 alkylene-arylene-S-, -arylene-C1-C10 alkylene-S-, -C1-C10 alkylene-(C3-C8 carbocyclo)-S-, - (C3-C8 carbocyclo)-C1-C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-; subscript k is an integer ranging from 1 to 36; R17 is optionally substituted by a Basic Unit (BU) such as an aminoalkyl moiety, e.g. –(CH2 )xNH2, –(CH2 )xNHRa, and –(CH2 )xNRa 2, wherein x is an integer of from 1-4 and each Ra is independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or two Ra groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group; and the wavy line indicates the point of covalent attachment to the rest of the Drug-Linker compound.
42. The Drug-Linker of any one of claims 37-41, or a salt thereof, wherein the Stretcher Unit Z' is
Figure imgf000397_0001
, wherein the wavy lines indicate the point of covalent attachment to the rest of the Drug-Linker compound.
43. The Drug-Linker compound of any one of claims 37-42, or a salt thereof, wherein the Connector Unit A is
Figure imgf000397_0002
wherein each R100 is independently selected from hydrogen or -C1-C3 alkyl; R111 is independently selected from the group consisting of hydrogen, p- hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, - CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, - (CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, - (CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, - (CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-,
Figure imgf000398_0001
each subscript c is an independently selected integer from 1 to 10; and the wavy lines indicate attachment of the Connector Unit to the rest of the Drug-Linker compound.
44. The Drug-Linker compound of any one of claims 37-43, or a salt thereof, wherein the Connector Unit A is
Figure imgf000398_0002
c is an integer ranging from 1 to 6; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof.
45. The Drug-Linker compound of any one of claims 37-42, or a salt thereof, wherein A is a bond.
46. The Drug-Linker compound of claims 37-45, or a salt thereof, wherein B is
Figure imgf000398_0003
each AA is independently a proteinogenic or non-proteinogenic amino acid; and the wavy lines indicate points of attachment to the rest of the Drug-Linker compound or salt thereof.
47. The Drug-Linker compound of any one of claims 37-46, or a salt thereof, wherein B is an amino acid.
48. The Drug-Linker compound of any one of claims 37-47, or a salt thereof, wherein B is
Figure imgf000399_0001
the wavy line indicates the point of attachement to the Partitioning Agent S*; and the asterisks indicate points of attachment to the rest of the Drug-Linker structure.
49. The Drug-Linker compound of any one of claims 37-48, or a salt thereof, wherein the Partitioning Agent S* is a polyethylene glycol (PEG) unit, cyclodextrin unit, polyamide, hydrophilic peptide, polysaccharide, or dendrimer.
50. The Drug-Linker compound of any one of claims 37-49, or a salt thereof, wherein the Partitioning Agent S* is a PEG Unit comprising from 4 to 72 (CH2CH2O) subunits.
51. The Drug Linker of any one of claims 37-50, or a salt thereof, wherein the PEG Unit is
Figure imgf000400_0001
; b is selected from the group consisting of 4 to 36; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof.
52. The Drug-Linker compound of any one of claims 37-51, or a salt thereof, wherein the Releasable Linker RL is –(AA)1-12–; and each AA is independently a proteinogenic or non-proteinogenic amino acid.
53. The Drug-Linker compound of any one of claims 37-52, or a salt thereof, wherein the Releasable Linker RL is –AA1-AA2– or –AA1-AA2-AA3–, wherein AA1 is attached to the Stretcher Unit Z' or the Connector Unit A.
54. The Drug-Linker compound of any one of claims 37-53, or a salt thereof, wherein the Releasable Linker RL is
Figure imgf000400_0002
the wavy line adjacent to the -NH- group indicates attachment to the Stretcher Unit Z' or the Connector Unit A and the wavy line adjacent to the -C(=O)- group indicates attachment to the Spacer Unit Y or the Drug Unit D.
55. The Drug-Linker compound of any one of claims 37-54, or a salt thereof, wherein the Releasable Linker RL is a glycoside.
56. The Drug-Linker compound of any one of claims 37-55, or a salt thereof, wherein the Releasable Linker RL is
Figure imgf000401_0001
wherein Su is a hexose form a monosaccharide; O' represents the oxygen atom of a glycosidic bond that is capable of cleavage by a glycosidase; the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.
57. The Drug-Linker compound of any one of claims 37-56, or a salt thereof, wherein the Releasable Linker RL is
Figure imgf000401_0002
the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.
58. The Drug-Linker compound of any one of claims 37-39 or 41-57, or a salt thereof, wherein the Spacer Unit Y is
Figure imgf000402_0001
wherein EWG is an electron-withdrawing group; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof.
59. The Drug-Linker compound of any one of claims 37-39 or 41-58, or a salt thereof, wherein the Spacer Unit Y is
Figure imgf000402_0002
the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof.
60. The Drug-Linker compound of any one of claims 37, 41-42, 45-48, 52-54, or 58-59, or a salt thereof, wherein
Figure imgf000402_0003
A is a bond; RL is –AA1-AA2–; AA1 and AA2 are each independently a proteinogenic amino acid;
Figure imgf000403_0001
the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or salt thereof.
61. The Drug-Linker compound of any one of claims 37, 41-42, 45-48, 52-54, or 58-60, or a salt thereof, wherein
Figure imgf000403_0002
.
62. The Drug-Linker compound of any one of claims 37-38 or 41-61, wherein Y- D is
Figure imgf000403_0003
the wavy line indicates the site of attachment to the rest of the Drug-Linker compound or salt thereof.
63. The Drug-Linker compound of any one of claims 37-38 or 41-61, wherein Y- D is
Figure imgf000404_0001
the wavy line indicates the site of attachment to the rest of the Drug-Linker compound or salt thereof.
64. The Drug-Linker compound of any one of claims 37, 41-42, 45-48, 52-54, 58- 61, or 62, wherein the compound is
Figure imgf000404_0002
or a salt thereof.
65. The Drug-Linker compound of any one of claims 37, 41-42, 45-48, 52-54, 58- 61, or 63, wherein the compound is
Figure imgf000405_0001
or a salt thereof.
66. A Ligand-Drug Conjugate compound of the formula: L-(Q-D)p or a pharmaceutically acceptable salt thereof, wherein L is a Ligand Unit; Q is a Linker Unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-A-S*-RL-, (iv) Z'-A-S*-RL-Y-, (v) Z'-A-B(S*)-RL-, (vi) Z'-A-B(S*)-RL-Y-, (vii) Z'-A-, (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-; Z' is a Stretcher Unit; A is a bond or a Connector Unit; B is a Parallel Connector Unit; S* is a Partitioning Agent; RL is a Releasable Linker; W is a Amino Acid Unit; Y is a Spacer Unit; and D is a Drug Unit of Formula (I'):
Figure imgf000406_0001
wherein Xb is -NR2-# or -N+R1R5-#, wherein the # denotes the point of attachment to Q, and Xa ken together with the carbon atom to which they are attached to form
Figure imgf000406_0002
, wherein the asterisk denotes the carbon atom of Formula (I) that bears the Xa and Xb groups, and the # denotes the point of attachment to Q; R1 and R5 are independently C1-C4 alkyl; X is H, OH, -C(O)NRaRb, -S(O)2Ra, -S(O)-Ra -S(O)2NRaRb, -NHS(O)2Ra, or -NHC(O)Ra; R2, R3, R4, R10, Ra, and Rb are each independently H or C1-C4 alkyl; R6 is C1-C4 alkyl optionally substituted with OH; R7 is H, C1-C4 alkyl optionally substituted with one or two OH moieties, or 5-6 membered heteroaryl; E is phenyl or 5-6 membered heteroaryl; R8, R9, and R11 are each independently H or OH; n is 0, 1, 2, or 3; m is 1, 2, 3, or 4; q is 0 or 1; p is an integer ranging from 1 to 12; and wherein when X is H, at least two of R7, R8, R9, and R11 comprise an OH moiety.
67. The Ligand-Drug Conjugate compound of claim 66, or a pharmaceutically acceptable salt thereof, wherein the Linker Unit Q is of formula (i), (ii), (iii), (iv), (x), or (xi).
68. The Ligand-Drug Conjugate compound of claim 66, or a pharmaceutically acceptable salt thereof, wherein the Linker Unit Q is of formula (v), (vi), (ix), or (xi).
69. The Ligand-Drug Conjugate compound of claim 66, or a pharmaceutically acceptable salt thereof, wherein the Linker Unit Q is of formula (viii), (ix), (x), or (xi).
70. The Ligand-Drug Conjugate compound of any one of claims 66-69, or a pharmaceutically acceptable salt thereof, wherein the Ligand Unit L and the Stretcher Unit Z together are
Figure imgf000407_0001
, wherein R17 is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O-(C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3- C8 heterocyclo-, -C1-C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene- , -C1-C10 alkylene-C(=O)-, C1-C10 heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O- (C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8 heterocyclo)-C(=O)-, - (C3-C8 heterocyclo)-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-NH-, C1-C10 heteroalkylene- NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene- arylene-NH-, -arylene-C1-C10 alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, -(C3- C8 carbocyclo)-C1-C10 alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, -C3-C8 carbocyclo-S -, -O-(C1-C8 alkylene)-S -, -arylene-S-, -C1-C10 alkylene-arylene-S-, -arylene-C1-C10 alkylene-S-, -C1-C10 alkylene-(C3-C8 carbocyclo)-S-, - (C3-C8 carbocyclo)-C1-C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-; subscript k is an integer ranging from 1 to 36; R17 is optionally substituted by a Basic Unit (BU) such as an aminoalkyl moiety, e.g. –(CH2 )xNH2, –(CH2 )xNHRa, and –(CH2 )xNRa 2, wherein x is an integer of from 1-4 and each Ra is independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or two Ra groups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group; and the wavy line indicates the point of covalent attachment to the rest of the Ligand-Drug Conjugate compound.
71. The Ligand-Drug Conjugate compound of any one of claims 66-70, or a pharmaceutically acceptable salt thereof, wherein the Ligand Unit L and the Stretcher Unit Z together are
Figure imgf000409_0001
Figure imgf000410_0001
wherein the wavy lines indicate the point of covalent attachment to the rest of the Ligand-Drug Conjugate compound.
72. The Ligand-Drug Conjugate compound of any one of claims 66-71, or a pharmaceutically acceptable salt thereof, wherein the Connector Unit A is
Figure imgf000411_0001
wherein each R100 is independently selected from hydrogen or -C1-C3 alkyl; R111 is independently selected from the group consisting of hydrogen, p- hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, - CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, - (CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, - CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-,
Figure imgf000411_0002
each subscript c is an independently selected integer from 1 to 10; and the wavy lines indicate attachment of the Connector Unit to the rest of the Ligand- Drug Conjugate compound or pharmaceutically acceptable salt thereof.
73. The Ligand-Drug Conjugate compound of any one of claims 66-72, or a pharmaceutically acceptable salt thereof, wherein the Connector Unit A is
Figure imgf000412_0001
c is an integer ranging from 1 to 6; and the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
74. The Ligand-Drug Conjugate compound of any one of claims 66-71, or a pharmaceutically acceptable salt thereof, wherein A is a bond.
75. The Ligand-Drug Conjugate compound of claims 66-74, or a salt thereof, wherein B is
Figure imgf000412_0002
each AA is independently a proteinogenic or non-proteinogenic amino acid; and the wavy lines indicate points of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
76. The Ligand-Drug Conjugate compound of any one of claims 66-75, or a pharmaceutically acceptable salt thereof, wherein B is an amino acid.
77. The Ligand-Drug Conjugate compound of any one of claims 66-76, or a pharmaceutically acceptable salt thereof, wherein B is
Figure imgf000412_0003
the wavy line indicates the point of attachement to the Partitioning Agent S*; and the asterisks indicate points of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
78. The Ligand-Drug Conjugate compound of any one of claims 66-77, or a pharmaceutically acceptable salt thereof, wherein the Partitioning Agent S* is a polyethylene glycol (PEG) unit, cyclodextrin unit, polyamide, hydrophilic peptide, polysaccharide, or dendrimer.
79. The Ligand-Drug Conjugate compound of any one of claims 66-78, or a pharmaceutically acceptable salt thereof, wherein the Partitioning Agent S* is a PEG Unit comprising from 4 to 72 (CH2CH2O) subunits.
80. The Ligand-Drug Conjugate compound of any one of claims 66-79, or a pharmaceutically acceptable salt thereof, wherein the PEG Unit is
Figure imgf000413_0001
; b is selected from the group consisting of 4 to 36; and the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
81. The Ligand-Drug Conjugate compound of any one of claims 66-80, or a pharmaceutically acceptable salt thereof, wherein the Releasable Linker RL is –(AA)1-12–; and each AA is independently a proteinogenic or non-proteinogenic amino acid.
82. The Ligand-Drug Conjugate compound of any one of claims 66-81, or a pharmaceutically acceptable salt thereof, wherein the Releasable Linker RL is –AA1-AA2– or –AA1-AA2-AA3–, wherein AA1 is attached to the Stretcher Unit Z or the Connector Unit A.
83. The Ligand-Drug Conjugate compound of any one of claims 66-82, or a pharmaceutically acceptable salt thereof, wherein the Releasable Linker RL is
Figure imgf000414_0001
the wavy line adjacent to the -NH- group indicates attachment to the Stretcher Unit Z or the Connector Unit A and the wavy line adjacent to the -C(=O)- group indicates attachment to the Spacer Unit Y or the Drug Unit D.
84. The Ligand-Drug Conjugate compound of any one of claims 66-83, or a pharmaceutically acceptable salt thereof, wherein the Releasable Linker RL is a glycoside.
85. The Ligand-Drug Conjugate compound of any one of claims 66-84, or a pharmaceutically acceptable salt thereof, wherein the Releasable Linker RL is
Figure imgf000414_0002
wherein Su is a hexose form a monosaccharide; O' represents the oxygen atom of a glycosidic bond that is capable of cleavage by a glycosidase; the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.
86. The Ligand-Drug Conjugate compound of any one of claims 66-85, or a pharmaceutically acceptable salt thereof, wherein the Releasable Linker RL is
Figure imgf000415_0001
the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.
87. The Ligand-Drug Conjugate compound of any one of claims 66-68 or 70-86, or a pharmaceutically acceptable salt thereof, wherein the Spacer Unit Y is
Figure imgf000415_0002
wherein EWG is an electron-withdrawing group; and the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
88. The Ligand-Drug Conjugate compound of any one of claims 66-68 or 70-87, or a pharmaceutically acceptable salt thereof, wherein the Spacer Unit Y is
Figure imgf000415_0003
the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
89. The Ligand-Drug Conjugate compound of any one of claims 66-67, 70-71, 74, 81-83, or 87-88, or a pharmaceutically acceptable salt thereof, wherein R17 is C1-C10 alkylene; A is a bond; RL is –AA1-AA2–; AA1 and AA2 are each independently a proteinogenic amino acid;
Figure imgf000416_0001
the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
90. The Ligand-Drug Conjugate compound of any one of claims 66-67, 70-71, 74, 81-83, or 87-89, or a pharmaceutically acceptable salt thereof, wherein A is a bond;
Figure imgf000416_0002
.
91. The Ligand-Drug Conjugate compound of any one of claims 66-67, 70-71, 74, 81-83, or 87-90, or a pharmaceutically acceptable salt thereof, wherein Y-D is
Figure imgf000417_0001
the wavy line indicates the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
92. The Ligand-Drug Conjugate compound of any one of claims 66-67, 70-71, 74, 81-83, or 87-90, or a pharmaceutically acceptable salt thereof, wherein Y-D is
Figure imgf000417_0002
the wavy line indicates the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.
93. The Ligand-Drug Conjugate compound of any one of claims 66-67, 70-71, 74, 81-83, or 87-91, wherein the compound is
Figure imgf000417_0003
, or
Figure imgf000418_0001
or a pharmaceutically acceptable salt thereof.
94. The Ligand-Drug Conjugate compound of any one of claims 66-67, 70-71, 74, 81-83, 87-90, or 92, wherein the compound is
Figure imgf000418_0002
Figure imgf000419_0001
or
Figure imgf000420_0001
or a pharmaceutically acceptable salt thereof.
95. The Ligand-Drug Conjugate compound of any one of claims 66-94, wherein p is an integer ranging from 2 to 8.
96. The Ligand-Drug Conjugate compound of any one of claims 66-95, wherein p is 4.
97. A pharmaceutical composition comprising the Ligand-Drug Conjugate compound of any one of claims 66-94 and a pharmaceutically acceptable excipient.
98. The pharmaceutical composition of claim 97, wherein the composition comprises a plurality of Ligand-Drug Conjugate compounds with an average drug-loading from 2 to 8.
99. The pharmaceutical composition of claim 98, wherein the average drug loading is about 4.
100. The pharmaceutical composition claim 98, wherein the average drug loading is from 3.5 to 4.5.
101. A method of treating cancer comprising administering a therapeutically effective amount of the Ligand-Drug Conjugate compound of any one of claims 66-96, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
102. The method of claim 101, wherein the subject tolerates treatment from the Ligand-Drug Conjugate compound better than another Ligand-Drug Conjugate compound in therapeutically effective doses.
103. The method of claim 102, wherein the another Ligand-Drug Conjugate compound comprises a monomethyl auristatin E or monomethyl auristatin F Drug Unit.
104. A compound, wherein the compound is selected from the group consisting of the compounds listed in Table 1 or a salt thereof.
105. A Drug-Linker compound, wherein the Drug-Linker compound is selected from the group consisting of the compounds listed in Table 2 or a salt thereof.
106. A Ligand-Drug Conjugate compound, wherein the Ligand-Drug Conjugate compound is selected from the group consisting of the compounds listed in Table 3, or a salt thereof, and p is an integer ranging from 1 to 12.
107. The Ligand-Drug Conjugate compound of any one of claims 66-96 or 106, wherein L is an antibody.
108. The Ligand-Drug Conjugate compound of any one of claims 66-96 or 106- 107, wherein L comprises an amino acid sequence that is at least 80% identical to the amino acid sequence of any one of SEQ ID Nos. 1 to 1044.
109. The Ligand Drug-Conjugate of any one of claims 66-96 or 106-108, wherein L comprises an amino acid sequence that is at least 85% identical to the amino acid sequence of any one of SEQ ID Nos. 1 to 1044.
110. The Ligand Drug-Conjugate of any one of claims 66-96 or 106-109, wherein L comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of any one of SEQ ID Nos. 1 to 1044.
111. The Ligand Drug-Conjugate of any one of claims 66-96 or 106-110, wherein L comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of any one of SEQ ID Nos. 1 to 1044.
112. The Ligand Drug-Conjugate of any one of claims 66-96 or 106-111, wherein L comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of any one of SEQ ID Nos. 1 to 1044.
113. The Ligand Drug-Conjugate of any one of claims 66-96 or 106-112, wherein L comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of any one of SEQ ID Nos. 1 to 1044.
114. The Ligand-Drug Conjugate compound of any one of claims claim 66-96 or 106-113, wherein L comprises the amino acid sequence of any one of SEQ ID Nos. 1 to 1044.
115. The Ligand-Drug Conjugate compound of any one of claims 66-96 or 106- 114, wherein L consists of the amino acid sequence of any one of SEQ ID Nos. 1 to 1044.
116. The Ligand-Drug Conjugate of any one of claims 66-96 or 106-115, wherein p is 8.
117. The Ligand-Drug Conjugate of any one of claims 66-96 or 106-115, wherein p is and integer from 1 to 8.
118. A Ligand-Drug Conjugate of the following formula:
Figure imgf000422_0001
wherein L is an anti-gpNMB antibody, and p is an integer from 1 to 14, or from 1 to 8, or is 8.
119. The Ligand-Drug Conjugate of claim 118, wherein the anti-gpNMB antibody comprises an amino acid sequence that is at least 80, 85, 90, 95, 98, or 99% identical to the amino acid sequence of any one of SEQ ID Nos. 935-944.
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